Selective androgen receptor degrader (sard) ligands and methods of use thereof

ABSTRACT

This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy&#39;s disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 62/150,763, filedon 21 Apr. 2015, U.S. Ser. No. 62/220,057, filed 17 Sep. 2015, U.S. Ser.No. 62/241,532, filed on 14 Oct. 2015, U.S. Ser. No. 62/220,187, filedon 17 Sep. 2015, and U.S. Ser. No. 62/219,859, filed on 17 Sep. 2015which are incorporated in their entirety herein by reference.

FIELD OF THE INVENTION

This invention is directed to novel indole, indazole, benzimidazole,indoline, quinolone, isoquinoline, and carbazole selective androgenreceptor degrader (SARD) compounds, pharmaceutical compositions and usesthereof in treating prostate cancer, advanced prostate cancer,castration resistant prostate cancer, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateralsclerosis (ALS), and uterine fibroids, and to methods for reducing thelevels of androgen receptor-full length (AR-FL) including pathogenicand/or resistance mutations, AR-splice variants (AR-SV), and pathogenicpolyglutamine (polyQ) polymorphisms of AR in a subject.

BACKGROUND OF THE INVENTION

Prostate cancer (PCa) is one of the most frequently diagnosednoncutaneous cancers among men in the US and is the second most commoncause of cancer deaths with more than 200,000 new cases and over 30,000deaths each year in the United States. PCa therapeutics market isgrowing at an annual rate of 15-20% globally.

Androgen-deprivation therapy (ADT) is the standard of treatment foradvanced PCa. Patients with advanced prostate cancer undergo ADT, eitherby luteinizing hormone releasing hormone (LHRH) agonists, LHRHantagonists or by bilateral orchidectomy. Despite initial response toADT, disease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). Up to 30% of patients withprostate cancer that undergo primary treatment by radiation or surgerywill develop metastatic disease within 10 years of the primarytreatment. Approximately 50,000 patients a year will develop metastaticdisease, which is termed metastatic CRPC (mCRPC).

Patients with CRPC have a median survival of 12-18 months. Thoughcastration-resistant, CRPC is still dependent on the androgen receptor(AR) signaling axis for continued growth. The primary reason for CRPCre-emergence is re-activation of AR by alternate mechanisms such as 1)intracrine androgen synthesis, 2) AR splice variants (AR-SV) that lackligand binding domain (LBD), 3) AR-LBD mutations with potential toresist AR antagonists (i.e., mutants that are not sensitive toinhibition by AR antagonists, and in some cases AR antagonists act asagonists of the AR bearing these LBD mutations); and 4) amplications ofthe AR gene within the tumor.

A critical barrier to progress in treating CRPC is that AR signalinginhibitors such as enzalutamide, flutamide, bicalutamide, andabiraterone, acting through the LBD, fail to inhibit growth driven bythe N-terminal domain (NTD)-dependent constitutively active AR-SV.Recent high-impact clinical trials with enzalutamide and abiraterone inCRPC patients demonstrated that 0% of AR-V7 (the predominant AR-SV)expressing patients responded to either of the treatments, indicatingthe requirement for next generation AR antagonists that target AR-SVs.In addition, a significant number of CRPC patients are becomingrefractory to abiraterone or enzalutamide, emphasizing the need for nextgeneration AR antagonists.

Current evidences demonstrate that CRPC growth is dependent onconstitutively active AR including AR-SV's that lack the LBD such asAR-V7 and therefore cannot be inhibited by conventional antagonists. ARinhibition and degradation through binding to a domain that is distinctfrom the AR LBD provides alternate strategies to manage CRPC.

Molecules that degrade the AR prevent any inadvertent AR activationthrough growth factors or signaling pathways, or promiscuousligand-dependent AR activation. In addition, molecules that inhibit theconstitutive activation of AR-SVs are extremely important to provideextended benefit to CRPC patients.

Currently only a few chemotypes are known to degrade AR which includethe SARDs AZD-3514, ARN-509 and ASC-J9. However, these molecules degradeAR indirectly at much higher concentrations than their bindingcoefficient and they fail to degrade the AR-SVs that have become inrecent years the primary reason for resurgence of treatment-resistantCRPC.

This invention describes novel AR antagonists with unique pharmacologythat strongly (high potency and efficacy) and selectively bind AR(better than known antagonists), antagonize AR, and degrade AR fulllength (AR-FL) and AR-SV. Selective androgen receptor degrader (SARD)compounds possess dual degradation and AR-SV inhibitory functions andhence are distinct from any available CRPC therapeutics. These novelselective androgen receptor degrader (SARD) compounds inhibit the growthof PCa cells and tumors that are dependent on AR-FL and AR-SV forproliferation.

SARDs have the potential to evolve as new therapeutics to treat CRPCsthat are untreatable with any other antagonists. This unique property ofdegrading AR-SV has extremely important health consequences for prostatecancer. Till date only one molecule (EPI-001) is reported to bind toAR-NTD and inhibit AR function and PCa cell growth, albeit at loweraffinity and it has an inability to degrade the receptor. The SARDs ofthis invention also bind AR-NTD and inhibit NTD-driven (i.e., ligandindependent) AR activity.

The positive correlation between AR and PCa and the lack of a fail-safeAR antagonist, emphasizes the need for molecules that inhibit ARfunction through novel or alternate mechanisms and/or binding sites, andthat can elicit antagonistic activities within an altered cellularenvironment.

Traditional antiandrogens such as bicalutamide and flutamide wereapproved for use in prostate cancer. Subsequent studies havedemonstrated the utility of antiandrogens (e.g., flutamide,spironolactone, cyproterone acetate, finasteride and chlormadinoneacetate) in androgen-dependent dermatological conditions such asandrogenic alopecia (male pattern baldness), acne vulgaris, andhirsutism. Prepubertal castration prevents sebum production andandrogenic alopecia but this can be reversed by use of testosterone,suggesting its androgen-dependence.

The AR gene has a polymorphism of glutamine repeats (polyQ) within exon1 which when shortened may augment AR transactivation (i.e.,hyperandrogenism). It has been found that shortened polyQ polymorphismsare more common in people with alopecia, hirsutism, and acne. Classicantiandrogens are undesirable for these purposes because they areineffective through dermal dosing and their long-term systemic useraises the risks of untoward sexual effects such as gynecomastia andimpotence. Further, similar to CRPC discussed above, inhibition ofligand-dependent AR activity alone may not be sufficient as AR can beactivated by various cellular factors other than the endogeneousandrogens testosterone (T) and dihydrotestosterone (DHT), such as growthfactors, kinases, co-activator overexpression and/or promiscuousactivation by other hormones (e.g., estrogens or glucocorticoids).Consequently, blocking the binding of T and DHT to AR with a classicalantiandrogen may not be sufficient to have the desired efficacy.

An emerging concept is the topical application of a SARD to destroy theAR localized to the affected areas of the skin or other tissue(s)without exerting any systemic antiandrogenism. For this use, a SARD thatdoes not penetrate the skin or is rapidly metabolized would bepreferrable.

Supporting this approach is the observation that cutaneous wound healinghas been demonstrated to be suppressed by androgens. Castration of miceaccelerates cutaneous wound healing while attenuating the inflammationin the wounds. The negative correlation between androgen levels andcutaneous healing and inflammation, in part, explains another mechanismby which high levels of endogenous androgens exacerbate hyperandrogenicdermatological conditions such those described herein. Further, itprovides a rationale for the treatment of wounds such as diabetic ulcersor even trauma, or skin disorders with an inflammatory component such asacne or psoriasis, with a topical SARD.

Androgenic alopecia occurs in ˜50% of Caucasian males by midlife and upto 90% by 80 years old. Minoxidil (a topical vasodilator) andfinasteride (a systemic 5-alpha reductase type II inhibitor) are FDAapproved for alopecia but require 4-12 months of treatment to produce atherapeutic effect and only arrest hair loss in most with mild tomoderate hair regrowth in 30-60%. Since currently available treatmentshave slow and limited efficacy that vary widely between individuals, andproduce unwanted sexual side effects, it is important to find a novelapproach to treat androgenic alopecia and other hyperandrogenicdermatologic diseases.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerativedisease. Patients with ALS are characterized by extended ARpolyglutamine repeats. Riluzole is an availlable drug for ALS treatment,however, only provides short-term effects. There is an urgent need fordrugs that extend the survival of ALS patients. Transgenic animals ofALS were shown to survive longer upon castration and reduction in ARlevels compared to castration+nandrolone (agonist) supplementation.Castration reduces the AR level, which may be the reason for extendedsurvival.

Androgens promote uterine proliferation. Higher testosterone levelsincrease the risk of uterine fibroids. Treatment of uterine fibroidswith SARDs would help prevent or treat uterine fibroids.

Here we describe indole, indazole, benzimidazole, indoline, quinolone,isoquinoline, and carbazole SARDs that bind to LBD and an alternatebinding and degradation domain (BDD; located outside the LBD, probablyin the NTD), antagonize AR, and degrade AR thereby blockingligand-dependent and ligand-independent AR activities. This novelmechanism produces improved efficacy when dosed systemically (e.g., forprostate cancer) or topically (e.g., dermatological diseases).

X-linked spinal-bulbar muscular atrophy (SBMA—also known as Kennedy'sdisease) is a muscular atrophy that arises from a defect in the androgenreceptor gene on the X chromosome. Proximal limb and bulbar muscleweakness results in physical limitations including dependence on awheelchair in some cases. The mutation results in a protractedpolyglutamine tract added to the N-terminal domain of the androgenreceptor (polyQ AR). Binding and activation of this lengthened polyQ ARby endogeneous androgens (testosterone and DHT) results in unfolding andnuclear translocation of the mutant androgen receptor. These steps arerequired for pathogenesis and result in partial loss of thetransactivation function (i.e., an androgen insensitivity) and a poorlyunderstood neuromuscular degeneration. Currently there are nodisease-modifying treatments but rather only symptom directedtreatments. Efforts to target the polyQ AR of Kennedy's disease as theproximal mediator of toxicity by harnessing cellular machinery topromote its degradation, i.e., through the use of a SARD, hold promisefor therapeutic intervention. Selective androgen receptor degraders suchas those reported herein bind to and degrade a variety of androgenreceptors (full length, splice variant, antiandrogen resistance mutants,and are likely to degrade polyQ AR polymorphisms as well), indicatingthat they are promising leads for treatment of SBMA.

SUMMARY OF THE INVENTION

In one embodiment, this invention provides a selective androgen receptordegrader (SARD) compound represented by the structure of formula I:

wherein

W₁ and W₂ are each independently selected from N or CH;

W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO, or OCN;R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;n is an integer between 1-3; andm is an integer between 1-3.

In another embodiment, W₁, W₂, W₃, W₄, W₅, and W₆ are CH. In anotherembodiment, W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH. In anotherembodiment, W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH. In anotherembodiment, W₁ is N and W₂, W₃, W₄, W₅, and W₆ are CH.

In another embodiment, the selective androgen receptor degrader (SARD)compound is represented by the structure of formula III:

wherein

-   -   T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In another embodiment, the selective androgen receptor degrader (SARD)compound is represented by the structure of formula V:

wherein Z, Y, R, Q, R₁, R₂, R₃, R₄, T, m and n are as described in thestructure of formula III; and l is 0 or 1; and k is 0, 1 or 2.

In another embodiment, the selective androgen receptor degrader (SARD)compound is represented by the structure of formula VI:

wherein Z, Y, R, Q, R₁, R₂, R₃, R₄, T, m and n are as described in thestructure of formula III.

In another embodiment, the selective androgen receptor degrader (SARD)compound is represented by the structure of formula VII:

wherein Z, Y, R, Q, R₁, R₂, R₃, R₄, T, m and n are as described in thestructure of formula III.

In another embodiment, the selective androgen receptor degrader (SARD)compound is represented by the structure of formula IV:

wherein Z, Y, R, Q, R₁, R₂, R₃, R₄, T, m and n are as described in thestructure of formula III.

In another embodiment, the SARD compound of this invention isrepresented by the structure of any one of the following compounds:

Indoles:

Benzimidazoles:

Pyrrolo-Pyridine:

Indazoles:

Indolines:

Isoquinolines and Quinolines:

In another embodiment, the compound of this invention binds to the ARthrough an alternate binding and degradation domain (BDD). In anotherembodiment, some of the compounds of this invention further bind the ARligand binding domain (LBD). In another embodiment, the compoundexhibits AR-splice variant (AR-SV) degradation activity. In anotherembodiment, the compound further exhibits AR-full length (AR-FL)degradation activity. In another embodiment, the compound exhibits AR-SVinhibitory activity (i.e., is an AR-SV antagonist). In anotherembodiment, the compound further exhibits AR-FL inhibitory activity(i.e., is an AR-FL antagonist). In another embodiment, the compoundpossesses dual AR-SV degradation and AR-SV inhibitory functions. Inanother embodiment, the compound further possesses dual AR-FLdegradation and AR-FL inhibitory functions.

In one embodiment, this invention is directed to a pharmaceuticalcomposition comprising a SARD compound according to this invention, orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof, and a pharmaceuticallyacceptable carrier. In another embodiment, the pharmaceuticalcomposition is formulated for topical use. In another embodiment, thepharmaceutical composition is in the form of a solution, lotion, salve,cream, ointment, liposome, spray, gel, foam, roller stick, cleansingsoaps or bars, emulsion, mousse, aerosol, shampoo, or any combinationthereof.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound according to this invention, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the prostatecancer is advanced prostate cancer, castration resistant prostate cancer(CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risknmCRPC or any combination therof.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of advanced prostate cancer and its symptoms,or increasing the survival of a male subject suffering from advancedprostate cancer comprising administering to said subject atherapeutically effective amount of a compound of this invention, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of a male subjectsuffering from castration resistant prostate cancer comprisingadministering to said subject a therapeutically effective amount of acompound of this invention, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.

In another embodiment, the prostate cancer depends on AR-SV forproliferation. In another embodiment, the prostate cancer furtherdepends on AR-FL for proliferation. In another embodiment, the AR-SV isAR-V7 or ARv567es. In another embodiment, the prostate cancer depends onAR that contains the W741L mutation or T877A mutation or otherantiandrogen resistance-conferring AR-LBD mutations, or any combinationthereof. In another embodiment, the prostate cancer depends onamplications of the AR gene within the tumor. In another embodiment,there may be a heterogenous expression of AR such that the prostatecancer may depend on multiple AR variations and/or amplifications withina single patient. In another embodiment, the subject further receivesandrogen deprivation therapy (ADT). In another embodiment, the subjecthas failed androgen deprivation therapy (ADT). In another embodiment,the cancer is resistant to treatment with an androgen receptorantagonist. In another embodiment, the androgen receptor antagonist isenzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514,galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproteroneacetate, ketoconazole, spironolactone, or any combination thereof. Inanother embodiment, the administering of the compound reduces the levelsof AR, AR-full length (AR-FL), AR-FL with antiandrogenresistance-conferring AR-LBD mutations, AR-splice variant (AR-SV),gene-amplified AR, or any combination therof, in said subject.

In one embodiment, this invention is directed to a method of reducingthe levels of AR-splice variants in a subject, comprising administeringto said subject a therapeutically effective amount of a compound of thisinvention, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the method further reduces the levels of AR-fulllength in said subject. In another embodiment, the reduction is achievedby degradation, inhibition, or dual degradation and inhibitory functionof AR-splice variants (AR-SV) or AR-FL variations including antiandrogenresistance mutants such as W741L and T877A. In another embodiment, thereduction is further achieved by degradation, inhibition, or dualdegradation and inhibitory function of AR-FL. In another embodiment, thereduction is further achieved by degradation or inhibition of AR fromamplified AR gene within the tumor.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of the Kennedy's disease in a subject,comprising administering to said subject a compound of this invention.

In one embodiment, this invention is directed to a method of reducingthe levels of polyglutamine (polyQ) AR polymorphs in a subjectcomprising administering a compound according to this invention. Inanother embodiment, the reduction is achieved by degradation,inhibition, or dual degradation and inhibitory function of saidpolyglutamine (polyQ) AR polymorphs (polyQ-AR). In another embodiment,the polyQ-AR is a short polyQ polymorph or a long polyQ polymorph. Inanother embodiment, the polyQ-AR is a short polyQ polymorph, and themethod further treats dermal disease. In another embodiment the polyQ-ARis a long polyQ polymorph, and said method further treats Kennedy'sdisease.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering a therapeutically effective amount ofthe compound of this invention, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof; or a pharmaceutical composition thereof.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering a therapeutically effective amount of the compound of thisinvention, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof;or a pharmaceutical composition thereof.

In one embodiment, this invention is directed to a method of: (a)treating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne in a subject; (b) decreasing sebumproduction in a subject; (c) treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofhirsutism in a subject; (d) treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofalopecia in a subject; (e) treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression of ahormonal condition in female; (f) treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofsexual perversion, hypersexuality, or paraphilias in a subject; (g)treating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis in a subject; (h)treating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of virilization in a subject; (i) treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndrome in asubject; (j) increasing, modulating, or improving ovulation in ananimal; (k) treating, suppressing, reducing the incidence, reducing theseverity, or inhibiting the progression of cancer in a subject; (l)treating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS); (m)treating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids or any combinationthereof, comprising administering a compound of this invention or apharmaceutical composition thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1A-FIG. 1C presents inhibition of AR transactivation for the SARDcompounds: (FIG. 1A) 14, 18, and 20; (FIG. 1B) 11 and 12; and (FIG. 1C)1123 and 27; of this invention.

FIG. 2A demonstrates degradation in LNCaP cells using SARD compounds ofthis invention (11 and 20): LNCaP cells were plated in 6 well plates at1 million cells/well. The cells were maintained in serum free conditionsfor 3 days. The cells were treated as indicated in the figure,harvested, protein extracted, and Western blotted for AR. FIG. 2Bpresents the effect of AR antagonists and SARD 11 on LNCaP cell growth:LNCaP cells were plated in 96 well plates at 10,000 cells/well inRPMI+1% csFBS without phenol red. Cells were treated as indicated in thefigure in combination with 0.1 nM R1881 for 6 days with medium change onday 3. At the end of 6 days, the cells were fixed and stained withsulphorhodamine blue stain.

FIG. 3 presents AR-V7 degradation (PC3-AR-V7 cells) using SARD compoundsof this invention (11, 12 and 20). PC-3 prostate cancer cells were serumstably transfected with a lentivirus construct for AR-V7. Once thestable cells were selected, the cells were plated in 6 well plates at 1million cells/well. The cells were treated as indicated in the figure(μM) and Western blot performed for AR and actin. The results show thatthe SARDs have the potential to degrade truncated versions of AR suchAR-V7, while enzalutamide or ARN-509 have no effect of the AR-V7expression, suggesting that SARDs of this invention, unlike enzalutamideand ARN-509, can treat AR-V7 dependent CRPC.

FIG. 4 demonstrates via Western blot that 20 degraded AR-FL and AR-SV in22RV-1 cells, further supporting their use in the treatment ofAR-SV-driven CRPC.

FIG. 5 presents SARD degradation of AR in LNCaP cells using 11.

FIG. 6A-FIG. 6C presents SARD degradation of AR-FL and AR-V7 in 22RV-1cells using (FIG. 6A) ASC-J9, (FIG. 6B) ARN-509 and (FIG. 6C) 11.

FIG. 7A-FIG. 7D present that 11 inhibits transactivation ofAR-NTD-DBD-hinge (A/BCD) AR construct which lacks the LBD. (FIG. 7A) ARA/BCD increases GRE-LUC reporter activity. AR A/BCD construct that lacksthe ligand binding domain or empty vector was transfected into HEK-293cells along with GRE-LUC and CMV-renilla LUC. Forty eight hours aftertransfection cells were harvested and luciferase assay performed. (FIG.7B) AR A/BCD activity was inhibited by 11. The A/BCD AR construct thatlacks the ligand binding domain (LBD) was transfected along with GRE-LUCand CMV-LUC. Cells were treated 24 hrs after transfection as indicatedin the figure and luciferase assay performed 48 hrs after transfection.11 (a SARD) inhibited the activity of construct lacking LBD confirmingthe binding to an alternate site in addition to the LBD. (FIG. 7C) and(FIG. 7D) Non-SARD antagonists ARN-509 and enzalutamide did not inhibitthe activity of this AR construct lacking the LBD, suggesting that ofthe compounds tested, only SARDs of this invention have the ability toinhibit ligand independent AR activity.

FIG. 8A-FIG. 8B presents data comparing compounds 11, 12, and 14 withgaleterone, EPI-001, and enzalutamide in AR transactivation studies.(FIG. 8A) 11, 12, and 14, galeterone, EPI-001, and enzalutamide; and(FIG. 8B) 11, galeterone, and enzaluatamide. SARDs of this inventionmore potently inhibited (AR-FL) transaction.

FIG. 9A-FIG. 9D demonstrates that 11 inhibited tumor growth of anaggressive prostate cancer (22RV-1) that expresses an AR splice variant(growth driven by AR-V7). (FIG. 9A) 11 significantly reduced tumorvolume and (FIG. 9B) tumor weight in a 22RV-1 xenograft tumor study,whereas AR antagonist enzalutamide did not have any effect compared tovehicle. (FIG. 9C) shows tumor expressed levels of AR-FL and AR-V7 weredecreased by 11 but not enzalutamide, demonstrating that in vivoactivity correlated with AR degradation in the tumors; and (FIG. 9D)demonstrates an in vivo antiandrogenic tone in gene expression as theserum PSA in these animals was decreased by 11 but not enzalutamide inthis 22RV-1 xenograft study.

FIG. 10A-FIG. 10C demonstrates that 11 inhibited LNCaP tumor xenograftgrowth via (FIG. 10A) decreased tumor volume and (FIG. 10B) weights, and(FIG. 10C) serum PSA levels in animals treated with 11 when compared tovehicle.

FIG. 11 presents degradation in LNCaP cells using 27, 20, 12, 23 and 32.LNCaP cells were plated in 6 well plates at 1 million cells/well. Thecells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. SARDs demonstrated selective degradation ofAR (i.e., SARD activity) in the nM range, i.e., at concentrationscomparable to their antagonist IC₅₀ values. LNCaP cells are known toexpress the AR mutant T877A, demonstrating the ability to degraderesistance conferring mutant androgen receptors.

FIG. 12 presents 22RV-1 Western blots: 22RV-1 cells were plated in 6well plates at 1-1.5 million cells/well in growth medium (RPMI+10% FBS).Next day, medium was changed and treated with vehicle or a dose responseof compounds 20, 24 and 30. After overnight treatment (12-16 hrs), cellswere washed in ice cold PBS and harvested by scrapping in 1 mL PBS.Cells were pelleted, protein extracted, quantified using BCA assay, andequal quantity of protein was fractionated on a SDS-PAGE. The proteinswere transferred to nylon membrane and Western blotted with AR antibody(N20 from SCBT) and actin antibody. Compounds 20, 24 and 30 were capableof degrading full length androgen receptor (AR-FL) and truncated AR(AR-SV) in 22RV-1 cells, suggesting that SARDs may be able to overcomewildtype or AR-V7 dependent prostate cancers.

FIG. 13 presents degradation in LNCaP cells (top) and 22RV-1 cells(bottom) using 31 vs. galeterone. Using the methods described in thelegends for FIG. 11 (LNCaP) and FIG. 12 (22RV-1), 31 was compared togaleterone (a clinical lead SARD). While 31 demonstrated SARD activityin both LNCaP (mutant AR harboring T877A mutation) and 22RV-1 (growthdependent on AR-SV lacking a LBD) cells, galeterone demonstrated littleto no AR degradation in these models.

FIG. 14 presents degradation in LNCaP cells using a dose-response of 12or ARN-509. Using the methods described in the legend for FIG. 11(LNCaP), SARD activity for 12 was compared to known SARD ARN-509. 12demonstrated activity in the nM range (100-1000 nM) whereas ARN-509 onlyhad activity at 10,000 nM.

FIG. 15 presents degradation in 22RV-1 cells using 31. Using the methodsdescribed in the legend for FIG. 12 (22RV-1), SARD activity for 31 wasdemonstrated as degradation of full length (AR) and truncated splicevariant (AR-V7) androgen receptor.

FIG. 16 presents degradation in LNCaP cells using 70 and 73. Using themethods described in the legend for FIG. 11 (LNCaP), SARD activity for70 and 73 was demonstrated at concentrations as low as 100 nM. Thisdemonstrates that benzimidazoles of this invention also demonstratepotent SARD activity.

FIG. 17A-FIG. 17C presents biophysical data that suggests that SARDsbind to the N-terminal domain of the AR (in addition to the LBD in theC-terminus). (FIG. 17A) and (FIG. 17B) A dose-dependent shift in thefluorescence intensity, i.e., fluorescent quenching, was observed with11 when incubated with AR AF-1. The fluorescence shoulder observed at307 nm, which corresponds to tyrosine residues in the AF-1, is shiftedby 11. The overall fluorescence is also markedly altered by 11. (FIG.17C) Data shown was plotted as difference in fluorescence betweencontrol and 11 treated samples (fluorescence in the absence ofcompound—fluorescence in the presence of compound), a dose dependentincrease was observed in the presence of 11. Cumulatively, these datasugest a direct interaction between 11 and AR AF-1.

FIG. 18 demonstrates degradation in LNCaP cells using a SARD compound ofthis invention (100). LNCaP cells were plated in 6 well plates at 1million cells/well. The cells were maintained in serum free conditionsfor 3 days. The cells were treated as indicated in the figure,harvested, protein extracted, and Western blotted for AR.

FIG. 19 demonstrates via Western blot as described above for FIG. 12,that 100, 102, and 130 degraded AR-FL and AR-SV in 22RV-1 cells. 100,102, and 130 were capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-SV) in 22RV-1 cells, suggesting thatindoline and isoquinoline SARDs of this invention may be able toovercome AR-V7 dependent prostate cancers.

FIG. 20 presents degradation in 22RV-1 cells as described above for FIG.12, using 130 vs. galeterone. 130 was compared to galeterone (a clinicallead SARD). 114 demonstrated SARD activity in 22RV-1 (growth dependenton AR-SV, an AR variant lacking a LBD) cells which was comparable togaleterone.

FIG. 21 presents degradation in LNCaP cells using 135 and 102. Using themethods described in the legend for FIG. 11, SARD activities for 135 and102 were demonstrated. These compounds partially to fully degradedmutant AR (T877A), suggesting that quinoline and indoline SARDs of thisinvention such as these may be useful in advanced prostate cancer and/orCRPC.

FIG. 22 presents degradation in LNCaP cells and 22RV-1 cells using 103and 104. Using the methods described in the legends for FIG. 11 (LNCaP)and FIG. 12 (22RV-1), 103 and 104 demonstrated SARD activity in bothLNCaP (mutant AR harboring T877A mutation) and 22RV-1 (growth dependenton AR-SV lacking a LBD) cells.

FIG. 23 presents degradation in 22RV-1 cells using 130. Using themethods described in the legend for FIG. 12, compound 130 demonstratedSARD activity at least at the 10 μM concentration.

FIG. 24 presents degradation in 22RV-1 cells using 134 and 130. Usingthe methods described in the legend for FIG. 12, compounds 134 and 130each demonstrated SARD activity at least at the 10 μM concentration.

FIG. 25 presents degradation in LNCaP cells using 101, 105, 106, 107 and108. Using the methods for FIG. 11 above, 101, 105, 106, 107 and 108each demonstrated the ability to degrade the AR in the nM range.

FIG. 26 depicts degradation in LNCaP cells using 200 and ARN-509. LNCaPcells treated with 200 were lyzed and subjected to Western blotanalysis, as described above.

FIG. 27 depicts degradation in 22RV-1 cells using 200 and 202. 22RV-1cells treated with 200 or 202 were lyzed and subjected to Western blotanalysis, as described above.

FIG. 28 depicts degradation in 22RV-1 cells using 202. 22RV-1 cellstreated with 202 were lyzed and subjected to Western blot analysis, asdescribed above.

FIG. 29A-FIG. 29O depicts transactivation data, binding, and AR-FL andAR-SV degradation for SARDs compounds of this invention. (FIG. 29A)presents transactivation data for 42 (IC₅₀=1015 nM) and binding (Ki=86.1nM). (FIG. 29B) presents transactivation data for 41 (IC₅₀=>10,000 nM)and binding (Ki=84.3 nM). (FIG. 29C) presents (1) transactivationdatafor 132 (IC₅₀=978.1 nM) and binding (Ki=353.2 nM); (2) AR fulllength degradation; and (3) AR splice variant degradation. (FIG. 29D)presents (1) transactivation data for 40 (IC₅₀=1032.1 nM) and binding(Ki=134.9 nM). (FIG. 29E) presents (1) transactivation data for 92(IC₅₀=946.8 nM) and binding (Ki=nM); (2) AR full length degradation; and(3) AR splice variant D567es degradation. (FIG. 29F) presents (1)transactivation data for 39 (IC₅₀=233.8 nM) and binding (Ki=719.9 nM);(2) AR full length degradation. (FIG. 29G) presents (1) transactivationdata for 38 (IC₅₀=318.4 nM) and binding (Ki=331.8 nM); (2) AR fulllength degradation; and (3) AR splice variant AR-V7 degradation. (FIG.29H) presents (1) transactivation data for 11 (IC₅₀=96.4 nM) and 37(IC₅₀=94.0 nM) and binding (Ki=252.6 nM); (2) AR full lengthdegradation; and (3) AR splice variant degradation. (FIG. 29I) presents(1) transactivation data for 36 (IC₅₀=1142.0 nM) and binding (Ki=315.3nM); (2) AR full length degradation. (FIG. 29J) presents (1)transactivation data for 115 (ICso=244.4 nM) and binding (Ki=71.5 nM);(2) AR full length degradation; and (3) AR splice variant AR-V7degradation. (FIG. 29K) presents (1) transactivation data for 35(ICso=98.47 nM (data not shown)) and binding (Ki=155.7 nM); (2) AR fulllength degradation. (FIG. 29L) presents (1) transactivation data for 205(IC₅₀=1079.1 nM) and binding (Ki=90.7 nM), (2) AR full lengthdegradation; and (3) AR splice variant AR-V7 degradation. (FIG. 29M)presents (1) transactivation data for 114 (IC₅₀=834.7 nM) and binding(Ki=204.4 nM); (2) AR full length degradation; and (3) AR splice variantAR-V7 degradation. (FIG. 29N) presents (1) transactivation data for 204(IC₅₀=1025.4 nM) and binding (Ki=809.6 nM). (FIG. 29O) presents (1)transactivation data for 34 (IC₅₀=nM) and binding (Ki=nM); (2) AR fulllength degradation; and (3) AR splice variant degradation.

FIG. 30A-FIG. 30D presents Hershberger assay: Mice (6-7 weeks old) weretreated with vehicle or indicated SARDs (100 mg/kg/day twice daily) for14 days orally. Animals were sacrificed and seminal vesicles weightswere recorded and represented. Results: (FIG. 30A) and (FIG. 30D) SARDsdemonstrated various degrees of decreased seminal vesicles weight, (FIG.30B) increased in body weight, and (FIG. 30C) decreased prostate weight.This behavior is consistent with an in vivo antiandrogenic effectexerted by SARDs of this invention.

FIG. 31 demonstrates that 103 slowed prostate cancer tumor growthdespite low levels in the plasma. SARD 103 selectively accumulated intumor. NSG mice were implanted with patient-derived prostate cancerxenografts. Animals were treated for 14 days and tumor volumes weremeasured twice weekly. Animals were sacrificed, 103 was extracted fromthe serum and tumor and measured using LC-MS/MS method. 103 selectivelyaccumulated in tumor with almost 10 times more tumor accumulation thanin plasma, possibly providing an explanation for anti-tumor activitydespite low levels of SARD in the plasma.

FIG. 32 presents data in a mouse xenograft model treated with 103 and36. The % change in tumor volume is presented using 103 and 36. LNCaPcells were implanted (5 million cells/mouse) in NSG mice. Once tumorsreach 70-200 mm³, animals were randomized and treated with SARDs (100mg/kg/twice daily). Tumor volume was measured at regular intervals andrepresented as % change from baseline.36 significantly inhibited tumorgrowth.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

Androgens act in cells by binding to the AR, a member of the steroidreceptor superfamily of transcription factors. As the growth andmaintenance of prostate cancer (PCa) is largely controlled bycirculating androgens, treatment of PCa heavily relies on therapies thattarget AR. Treatment with AR antagonists such as enzalutamide,flutamide, bicalutamide or hydroxyflutamide to disrupt receptoractivation has been successfully used in the past to reduce PCa growth.All currently available AR antagonists competitively bind AR and recruitcorepressors such as NCoR and SMRT to repress transcription of targetgenes. However, altered intracellular signaling, AR mutations, andincreased expression of coactivators lead to functional impairment ofantagonists or even transformation of antagonists into agonists. Studieshave demonstrated that mutation of W741 and T877 within AR convertsbicalutamide and hydroxyflutamide, respectively, to agonists. Similarly,increased intracellular cytokines recruit coactivators instead ofcorepressors to AR-responsive promoters subsequently convertingbicalutamide to an agonist.

Despite initial response to androgen deprivation therapy (ADT), PCadisease progression is inevitable and the cancer emerges as castrationresistant prostate cancer (CRPC). The primary reason for castrationresistant prostate cancer (CRPC) re-emergence is re-activation ofandrogen receptor (AR) by alternate mechanisms such as:

-   -   (a) intracrine androgen synthesis;    -   (b) expression of AR splice variants (AR-SV) that lack ligand        binding domain (LBD);    -   (c) AR-LBD mutations with potential to resist antagonists;    -   (d) hyper-sensitization of AR to low androgen levels, e.g., due        to AR gene amplification or AR mutation;    -   (e) amplication of the AR gene within the tumor; and    -   (f) over expression of coactivators.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which inhibit the growth ofprostate cancer (PCa) cells and tumors that are dependent on AR fulllength (AR-FL) including pathogenic and resistance-conferring mutationand/or wildtype, and/or AR splice variants (AR-SV) for proliferation.

According to this invention, a “selective androgen receptor degrader”(SARD) compound is an androgen receptor antagonist that is capable ofinhibiting the growth of PCa cells and tumors that are dependent onAR-full length (AR-FL) and/or AR splice variants (AR-SV) forproliferation. In another embodiment, the SARD compound does not bind tothe ligand binding domain (LBD). In another embodiment, the SARDcompound binds to the N-terminal domain (NTD) of the AR. In anotherembodiment, the SARD compound binds to an alternate binding anddegradation domain (BDD) of the AR. In another embodiment, the SARDcompound binds both to the AR ligand binding domain (LBD) and to analternate binding and degradation domain (BDD). In another embodiment,the SARD compound binds both to the N-terminal domain (NTD) and to theligand binding domain (LBD) of the AR. In another embodiment, the SARDcompound is capable of inhibiting growth driven by the N-terminal domain(NTD)-dependent constitutively active AR-SV. In another embodiment, theSARD compound inhibits the AR through binding to a domain that isdistinct from the AR LBD. In another embodiment, the SARD compound is astrong (i.e., highly potent and highly efficacious) selective androgenreceptor antagonist, which antagonizes the AR stronger than other knownAR antagonists (e.g., enzalutamide, flutamide, bicalutamide andabiraterone). In another embodiment, the SARD compound is a selectiveandrogen receptor antagonist, which targets AR-SVs, which cannot beinhibited by conventional antagonists. In another embodiment, the SARDcompound exhibits AR-splice variant (AR-SV) degradation activity. Inanother embodiment, the SARD compound further exhibits AR-full length(AR-FL) degradation activity. In another embodiment, the SARD compoundexhibits AR-splice variant (AR-SV) inhibitory activity (i.e., is anAR-SV antagonist). In another embodiment, the SARD compound furtherexhibits AR-full length (AR-FL) inhibitory activity (i.e., is an AR-FLantagonist). In another embodiment, the SARD compound possesses dualAR-SV degradation and AR-SV inhibitory functions. In another embodiment,the SARD compound further possesses dual AR-FL degradation and AR-FLinhibitory functions. In another embodiment, the SARD compound is aselective androgen receptor antagonist, which targets AR-SVs. In anotherembodiment, the SARD compound further targets AR-FLs. In anotherembodiment, the SARD compound inhibits the constitutive activation ofAR-SVs. In another embodiment, the SARD compound further inhibits theconstitutive activation of AR-FLs. In another embodiment, the SARDcompound is a selective androgen receptor antagonist, which degradesAR-full length (AR-FL) and AR splice variants (AR-SV). In anotherembodiment, the SARD compound degrades the AR through binding to adomain that is distinct from the AR LBD. In another embodiment, the SARDcompound possesses dual degradation and AR-SV inhibitory functions, thatare distinct from any available CRPC therapeutics. In anotherembodiment, the SARD compound inhibits the re-activation of the AR byalternate mechanisms such as: intracrine androgen synthesis, expressionof AR splice variants (AR-SV) that lack ligand binding domain (LBD) andAR-LBD mutations with potential to resist antagonists. In antoherembodiment, the SARD compound inhibits re-activated androgen receptorspresent in pathogenically altered cellular environments.

Nonlimiting examples of AR-splice variants (AR-SVs) are: AR-V7 andARv567es (a.k.a. AR-V12). Nonlimiting examples of AR mutationsconferring antiandrogen resistance are: W741L mutation and T877Amutation. AR-V7 is a splice variant of AR that lacks the LBD. It isconstitutively active and has been demonstrated to be responsible foraggressive PCa and resistance to endocrine therapy.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which bind to the ARthrough an alternate binding and degradation domain (BDD). In anotherembodiment, the SARD further binds the AR ligand binding domain (LBD).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) inhibitory activity (i.e., is an AR-SV antagonist). Inanother embodiment, the novel selective androgen receptor degrader(SARD) compounds, further exhibit AR-full length (AR-FL) inhibitoryactivity (i.e., is an AR-FL antagonist).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) degradation activity. In another embodiment, the novelselective androgen receptor degrader (SARD) compounds, further exhibitAR-full length (AR-FL) degradation activity.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which possess dual AR-SVdegradation and AR-SV inhibitory functions. In another embodiment, theSARDs further possess dual AR-FL degradation and AR-FL inhibitoryfunctions. In another embodiment, this invention is directed to novelselective androgen receptor degrader (SARD) compounds, which possessdual AR-SV and AR-FL degradation, and AR-SV and AR-FL inhibitoryfunctions.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, for use in treating CRPCthat cannot be treated with any other antagonist.

In one embodiment, this invention is directed to selective androgenreceptor degrader (SARD) compounds, for use in treating CRPC, bydegrading AR-SVs.

In one embodiment, the novel SARD compounds according to this inventionmaintain their antagonistic activity in AR mutants that normally convertAR antagonists to agonists. In another embodiment, the SARD compoundsmaintain their antagonistic activity to AR mutants W741 and T877. Inanother embodiment, the SARD compounds elicit antagonistic activitywithin an altered cellular environment in which LBD-targeted agents arenot effective. In another embodiment, the SARD compounds elicitantagonistic activity within an altered cellular environment in whichNTD-dependent AR activity is constitutively active.

Selective Androgen Receptor Degrader (SARD) Compounds

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I:

wherein

-   -   W₁ and W₂ are each independently selected from N or CH;    -   W₃, W₄, W₅ and W₆ are each independently selected from CH or N;

wherein if any one of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H isoptionally replaced with R₄, Q or R₃ in the respective position, and ifany one of W₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respectiveposition is unsubstituted;

-   -   T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ and R₄ are independently selected from hydrogen, F, Cl, Br, I, CF₃,CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionally substitutedlinear or branched alkyl, optionally substituted linear or branchedheteroalkyl, optionally substituted aryl, optionally substituted phenyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted arylalkyl, C(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In another embodiment, W₁, W₂, W₃, W₄, W₅, and W₆ of formula I are eachindependently CH. In another embodiment, W₁ is N. In another embodiment,W₂ is N. In another embodiment, W₁ is CH. In another embodiment, W₂ isCH. In another embodiment, W₃ is N. In another embodiment, W₄ is N. Inanother embodiment, W₅ is N. In another embodiment, W₆ is N.

In another embodiment, W₁ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH. Inanother embodiment, W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH. Inanother embodiment, W₄ is N and W₁, W₂, W₃, W₅, and W₆ are CH. Inanother embodiment, W₅ is N and W₁, W₂, W₃, W₄, and W₆ are CH. Inanother embodiment, W₆ is N and W₁, W₂, W₃, W₄, and W₅ are CH.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula II:

wherein

is a single or double bond;

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula III:

wherein

-   -   T is OH, OR, —NHCOCH₃, NHCOR or

-   -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN or C(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR,        OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl,        O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl,        —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IV:

wherein

T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V:

wherein

-   -   T is OH, OR, —NHCOCH₃, NHCOR or

-   -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VI:

wherein

-   -   T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VII:

wherein

-   -   T is OH, OR, —NHCOCH₃, NHCOR or Y

-   -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto(═O), alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VIII:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

-   -   m is an integer between 1-3;    -   l is 0 or 1; and    -   k is 0, 1 or 2.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IXa, IXb, IXc or IXd:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; and

-   -   m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula X:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

m is an integer between 1-3;

l is 0 or 1; and

k is 0, 1 or 2.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIa, XIb, XIc or XId:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XII:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

l is 0 or 1; and

k is 0, 1 or 2.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIIIa, XIIIb, XIIIc or IIIId:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XIV:

wherein

T is OH, OR, —NHCOCH₃, or NHCOR;

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; and

m is an integer between 1-3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula XV:

wherein

Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF₃, F, I, Br, Cl, CN or C(R)₃;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R₂ is hydrogen, halogen, CN, NO₂, COOH, COOR, COR, NHCOR, CONHR, OH, OR,SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl,O—C₁-C₁₂-haloalkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl, arylalkyl, benzyl,aryl, or C₃-C₇-cycloalkyl;

Q is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

R₄ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy,haloalkyl, optionally substituted linear or branched alkyl, optionallysubstituted linear or branched heteroalkyl, optionally substituted aryl,optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR,OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR,OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN;

n is an integer between 1-3; andm is an integer between 1-3.

In one embodiment, Q of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is hydrogen. In one embodiment, Qof compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV and XV is halogen. In one embodiment, Q of compound of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is F. In oneembodiment, Q of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is Br. In one embodiment, Q of compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV isCl. In one embodiment, Q of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is I. In one embodiment, Q ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is CN. In one embodiment, Q of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is NO₂. In oneembodiment, Q of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is optionally substituted linear or branchedalkyl. In one embodiment, Q of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is CH₃. In one embodiment, Q ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is alkoxy. In one embodiment, Q of compound of formulas I-VI isOCH₃. In one embodiment, Q of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is CF₃. In one embodiment, Q ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is optionally substituted phenyl. In one embodiment, Q ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is unsubstituted phenyl.

In one embodiment, R₃ of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XIV and XV is hydrogen. In one embodiment, R₃ of compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XIV and XV is halogen. In oneembodiment, R₃ of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XIVand XV is F. In one embodiment, R₃ of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XIV and XV is Cl. In one embodiment, R₃ of compoundof formulas I-VIII, IXa-IXd, X, XIa-XId, XIV and XV is Br. In oneembodiment, R₃ of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XIVand XV is I. In one embodiment, R₃ of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XIV and XV is CN. In one embodiment, R₃ of compoundof formulas I-VIII, IXa-IXd, X, XIa-XId, XIV and XV is COOH. In oneembodiment, R₃ of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XIVand XV is NO₂. In one embodiment, R₃ of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XIV and XV is CF₃.

In one embodiment, R₄ of compound of formulas I-VII, XIV, XV ishydrogen. In one embodiment, R₄ of compound of formulas I-VII, XIV, XVis halogen. In one embodiment, R₄ of compound of formulas I-VII, XIV, XVis F. In one embodiment, R₄ of compound of formulas I-VII, XIV, XV isCl. In one embodiment, R₄ of compound of formulas I-VII, XIV, XV is Br.In one embodiment, R₄ of compound of formulas I-VII, XIV, XV is I. Inone embodiment, R₄ of compound of formulas I-III is CN. In oneembodiment, R₄ of compound of formulas I-VII, XIV, XV is COOH. In oneembodiment, R₄ of compound of formulas I-III is NO₂. In one embodiment,R₄ of compound of formulas I-III is CF₃. In one embodiment, R₄ ofcompound of formulas I-VII, XIV, XV is methyl. In one embodiment, R₄ ofcompound of formulas I-VII, XIV, XV is COOR.

In one embodiment, Z of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is CN. In another embodiment, Z ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is NO₂. In another embodiment, Z of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is COOH. In anotherembodiment, Z of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is COR. In another embodiment, Z of compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV isNHCOR. In another embodiment, Z of compound of formulas I-VIII, IXa-IXd,X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is CONHR. In anotherembodiment, Z of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is in the para position.

In one embodiment, Y of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is CF₃. In another embodiment, Yof compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV and XV is F. In another embodiment, Y of compound of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is I. Inanother embodiment, Y of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is Br. In another embodiment, Y ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV is Cl. In another embodiment, Y of compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV is CN. In anotherembodiment, Y of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is C(R)₃. In another embodiment, Y of compoundof formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV isin the meta position.

In one embodiment, Z of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is CN and Y is CF₃. In anotherembodiment, Z is NO₂ and Y is CF₃. In another embodiment, Z is NO₂ and Yis halogen. In another embodiment, Z is CN and Y is halogen. In anotherembodiment, Z of compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV and XV is in the para position and Y is in the metaposition.

In one embodiment, R₂ of compound of formulas I-VII, XIV and XV ishydrogen. In one embodiment, R₂ of compound of formulas I-VII, XIV andXV is halogen. In one embodiment, R₂ of compound of formulas I-VII, XIVand XV is CN. In one embodiment, R₂ of compound of formulas I-VII, XIVand XV is NO₂. In one embodiment, R₂ of compound of formulas I-VII, XIVand XV is C₁-C₁₂-alkyl. In one embodiment, R₂ of compound of formulasI-VII, XIV and XV is aryl. In one embodiment, R₂ of compound of formulasI-VII, XIV and XV is phenyl. In one embodiment, R₂ of compound offormulas I-VII, XIV and XV is COOH. In one embodiment, R₂ of compound offormulas I-VII, XIV and XV is COOR. In one embodiment, R₂ of compound offormulas I-VII, XIV and XV is COR. In one embodiment, R₂ of compound offormulas I-VII, XIV and XV is NHCOR. In one embodiment, R₂ of compoundof formulas I-VII, XIV and XV is CONHR. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is OH. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is OR. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is SH. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is SR. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is NH₂. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is NHR. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is N(R)₂. In one embodiment, R₂of compound of formulas I-VII, XIV and XV is C₁-C₁₂-haloalkyl. In oneembodiment, R₂ of compound of formulas I-VII, XIV and XV isO—C₁-C₁₂-alkyl. In one embodiment, R₂ of compound of formulas I-VII, XIVand XV is O—C₁-C₁₂-haloalkyl. In one embodiment, R₂ of compound offormulas I-III is —SO₂-aryl. In one embodiment, R₂ of compound offormulas I-VII, XIV and XV is —SO₂-phenyl. In one embodiment, R₂ ofcompound of formulas I-VII, XIV and XV is —CO-aryl. In one embodiment,R₂ of compound of formulas I-VII, XIV and XV is arylalkyl. In oneembodiment, R₂ of compound of formulas I-VII, XIV and XV is benzyl. Inone embodiment, R₂ of compound of formulas I-VII, XIV and XV isC₃-C₇-cycloalkyl.

In one embodiment, R₁ of compound of formulas I-VII and XIV is CH₃. Inanother embodiment, R₁ of compound of formulas I-VII and XIV is CF₃.

In one embodiment, T of compound of formulas I-VII and XIV is OH. Inanother embodiment, T of compound of formulas I-VII and XIV is OCH₃. Inanother embodiment, T of compound of formulas I-VII and XIV is

In one embodiment, R of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV is alkyl. In another embodiment, Ris haloalkyl. In another embodiment, R is dihaloalkyl. In anotherembodiment, R is trihaloalkyl. In another embodiment, R is CH₂F. Inanother embodiment, R is CHF₂. In another embodiment, R is CF₃. Inanother embodiment, R is CF₂CF₃. In another embodiment, R is aryl. Inanother embodiment, R is phenyl. In another embodiment, R is F. Inanother embodiment, R is Cl. In another embodiment, R is Br. In anotherembodiment, R is I. In another embodiment, R is alkenyl. In anotherembodiment, R is hydroxyl (OH).

In one embodiment, m of compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XIV and XV is 1. In one embodiment, m of compound of formulasI-VIII, IXa-IXd, X, XIa-XId, XIV and XV is 2. In one embodiment, m ofcompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XIV and XV is 3.

In one embodiment, n of compound of formulas I-VII, XIV and XV is 1. Inone embodiment, n of compound of formulas I-VII, XIV and XV is 2. In oneembodiment, m of compound of formulas I-VII, XIV and XV is 3.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound selected from the followingstructures:

Indoles:

Benzimidazoles:

Pyrrolo-Pyridine:

Indolines:

Isoquinolines and Quinolines:

Carbazoles:

The term “heterocycloalkyl” group refers, in one embodiment, to acycloalkyl structure comprising in addition to carbon atoms, sulfur,oxygen, nitrogen or any combination thereof, as part of the ring. Inanother embodiment, the heterocycloalkyl is a 3-12 membered ring. Inanother embodiment, the heterocycloalkyl is a 6 membered ring. Inanother embodiment, the heterocycloalkyl is a 5-7 membered ring. Inanother embodiment, the heterocycloalkyl is a 4-8 membered ring. Inanother embodiment, the heterocycloalkyl group may be unsubstituted orsubstituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido,alkylamido, dialkylamido, cyano, nitro, CO₂H, amino, alkylamino,dialkylamino, carboxyl, thio and/or thioalkyl. In another embodiment,the heterocycloalkyl ring may be fused to another saturated orunsaturated cycloalkyl or heterocyclic 3-8 membered ring. In anotherembodiment, the heterocyclic ring is a saturated ring. In anotherembodiment, the heterocyclic ring is an unsaturated ring. In anotherembodiment, the heterocycloalkyl is piperidine, tetrahydrofuran,morpholine, pyrrolidine, or piperazine.

The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclicring comprising carbon and hydrogen atoms. A cycloalkyl group can haveone or more carbon-carbon double bonds in the ring so long as the ringis not rendered aromatic by their presence. Examples of cycloalkylgroups include, but are not limited to, (C₃-C₇) cycloalkyl groups, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl,and saturated cyclic and bicyclic terpenes and (C₃-C₇) cycloalkenylgroups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclicterpenes. A cycloalkyl group can be unsubstituted or substituted by oneor two substituents. Preferably, the cycloalkyl group is a monocyclicring or bicyclic ring.

The term “alkyl” refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. In another embodiment, the cyclic alkyl group has 3-8carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons.In another embodiment, the branched alkyl is an alkyl substituted byalkyl side chains of 1 to 5 carbons. In another embodiment, the branchedalkyl is an alkyl substituted by haloalkyl side chains of 1 to 5carbons. The alkyl group may be unsubstituted or substituted by ahalogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thioand/or thioalkyl.

The term “heteroalkyl” refers to any alkyl as defined above wherein oneor more of the carbons are being replaced by oxygen, nitrogen, sulfur,phosphorous or combination thereof.

An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyland aryl are as defined above. An example of an arylalkyl group is abenzyl group.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bonds. The alkenyl group may have one doublebond, two double bonds, three double bonds, etc. In another embodiment,the alkenyl group has 2-12 carbons. In another embodiment, the alkenylgroup has 2-6 carbons. In another embodiment, the alkenyl group has 2-4carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl,cyclohexenyl, etc. The alkenyl group may be unsubstituted or substitutedby a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido,nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system. In another embodiment, the aryl isphenyl.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. It isunderstood by a person skilled in the art that when T, Q, R₂ R₃ or R₄ inthe compounds of the present invention is OR, then the corresponding Ris not OH.

In one embodiment, the term “halogen” or “halo” refers to a halogen,such as F, Cl, Br or I.

In one embodiment, this invention provides for the use of a compound asherein described and/or, its derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or combinations thereof.

In one embodiment, the methods of this invention make use of“pharmaceutically acceptable salts” of the compounds, which may beproduced, by reaction of a compound of this invention with an acid orbase.

Suitable pharmaceutically acceptable salts of amines of the compounds ofthe methods of this invention may be prepared from an inorganic acid orfrom an organic acid. In one embodiment, examples of inorganic salts ofamines are bisulfates, borates, bromides, chlorides, hemisulfates,hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates,persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonicacids (alkylsulfonates, arylsulfonates, halogen substitutedalkylsulfonates, halogen substituted arylsulfonates), sulfonates andthiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,algenates, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxylates, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonates,gluconates, glutamates, glycolates, glucorates, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamates, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates,hydrofluorates, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, nitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, pectinates, phenylpropionates, palmitates, pantothenates,polygalacturates, pyruvates, quinates, salicylates, succinates,stearates, sulfanilates, subacetates, tartarates, theophyllineacetates,p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates,undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earth metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procaine,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the methods of this invention make use of apharmaceutically acceptable salt of the compounds of this invention. Inone embodiment, the methods of this invention make use of apharmaceutically acceptable salt of compounds of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV. In one embodiment,the methods of this invention make use of a salt of an amine of thecompounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVand XV of this invention. In one embodiment, the methods of thisinvention make use of a salt of a phenol of the compounds of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV of thisinvention.

In one embodiment, the methods of this invention make use of a freebase, free acid, non charged or non-complexed compounds of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV and/or itsisomer, pharmaceutical product, hydrate, polymorph, or combinationsthereof.

In one embodiment, the methods of this invention make use of an isomerof a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV and XV. In one embodiment, the methods of this invention make use ofa pharmaceutical product of a compound of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV and XV. In one embodiment, the methods ofthis invention make use of a hydrate of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV. In one embodiment,the methods of this invention make use of a polymorph of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV and XV. Inone embodiment, the methods of this invention make use of a metaboliteof a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV and XV. In another embodiment, the methods of this invention makeuse of a composition comprising a compound of formulas I-VIII, IXa-IXd,X, XIa-XId, XII, XIIIa-XIIId, XIV and XV, as described herein, or, inanother embodiment, a combination of isomer, metabolite, pharmaceuticalproduct, hydrate, polymorph of a compound of formulas I-VIII, IXa-IXd,X, XIa-XId, XII, XIIIa-XIIId, XIV and XV.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the term “isomer” is meant to encompass opticalisomers of the SARD compound. It will be appreciated by those skilled inthe art that the SARDs of the present invention contain at least onechiral center. Accordingly, the SARDs used in the methods of the presentinvention may exist in, and be isolated in, optically-active or racemicforms. Some compounds may also exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARDs are the pure (R)-isomers. In another embodiment, the SARDs are thepure (S)-isomers. In another embodiment, the SARDs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARDs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

In another embodiment, this invention further includes hydrates of thecompounds. The invention also includes use of N-oxides of the aminosubstituents of the compounds described herein.

In one embodiment, the term “hydrate” refers to hemihydrate,monohydrate, dihydrate, trihydrate or others, as known in the art.

This invention provides, in other embodiments, use of metabolites of thecompounds as herein described. In one embodiment, “metabolite” means anysubstance produced from another substance by metabolism or a metabolicprocess.

In one embodiment, the compounds of this invention are preparedaccording to Examples 1-4.

Biological Activity of Selective Androgen Receptor Degraders

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by the structure of formula I-VIII, IXa-IXd, X, XIa-XId,XII, XIIIa-XIIId, XIV or XV as described above. pharmaceuticallyacceptable saltpharmaceutically acceptable saltpharmaceuticallyacceptable saltpharmaceutically acceptable saltpharmaceuticallyacceptable salt

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, flutamide, bicalutamide,abiraterone, ARN-509, AZD-3514, galeterone, ASC-J9, flutamide,hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole,spironolactone, or any combination thereof. In another embodiment,administering the compound to a subject reduces the levels of AR,AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferringAR-LBD mutations, AR-splice variant (AR-SV), gene-amplified AR, or anycombination thereof, in said subject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,selected from the following structures:

Indoles:

Benzimidazoles:

Pyrrolo-Pyridine:

Indazoles:

Indolines:

Isoquinolines and Quinolines:

Carbazoles:

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, flutamide, bicalutamide,abiraterone, ARN-509, AZD-3514, galeterone, ASC-J9, flutamide,hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole,spironolactone, or any combination thereof. In another embodiment,administering the compound to a subject reduces the levels of AR,AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferringAR-LBD mutations, AR-splice variant (AR-SV), gene-amplified AR, or anycombination thereof, in said subject.

In one embodiment, the methods of this invention are directed totreating, suppressing, reducing the incidence, reducing the severity,inhibiting, providing palliative care, or increasing the survival of asubject suffering from prostate cancer. In one embodiment, the methodsof this invention are directed to methods of treating, suppressing,reducing the incidence, reducing the severity, inhibiting, providingpalliative care, or increasing the survival of advanced prostate cancerin a subject. In one embodiment, the methods of this invention aredirected to treating, suppressing, reducing the incidence, reducing theseverity, inhibiting, providing palliative care, or increasing thesurvival of a subject suffering from castration resistant prostatecancer (CRPC). In one embodiment, the methods of this invention aredirected to treating, suppressing, reducing the incidence, reducing theseverity, inhibiting, providing palliative care, or increasing thesurvival of a subject suffering from metastatic castration resistantprostate cancer (mCRPC). In one embodiment, the methods of thisinvention are directed to treating, suppressing, reducing the incidence,reducing the severity, inhibiting, providing palliative care, orincreasing the survival of a subject suffering from non-metastaticcastration resistant prostate cancer (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC. In another embodiment, the subject has highor increasing prostate specific antigen (PSA) levels.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a SARD compound or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof, said compound is represented by a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV or any one of compounds11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of advanced prostate cancer and its symptoms,or increasing the survival of a male subject suffering from advancedprostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVor XV or any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93,100-115, 130-137, or 200-205.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of metastatic prostate cancer and itssymptoms, or increasing the survival of a male subject suffering frommetastatic prostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVor XV or any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93,100-115, 130-137, or 200-205.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of a male subjectsuffering from castration resistant prostate cancer (CRPC) comprisingadministering to said subject a therapeutically effective amount of aSARD compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,said compound is represented by a compound of formulas I-VIII, IXa-IXd,X, XIa-XId, XII, XIIIa-XIIId, XIV or XV or any one of compounds 11-27,30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used for treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of castration resistant prostate cancer (CRPC) and itssymptoms, or increasing the survival of men with castration resistantprostate cancer. In another embodiment, the CRPC is metastatic CRPC(mCRPC). In another embodiment, the CRPC is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. In anotherembodiment, the subject further receives androgen deprivation therapy.

As used herein, the terms “increase” and “prolong” may be usedinterchangeably having all the same meanings and qualities, whereinthese terms may in one embodiment refer to a lengthening of time. Inanother embodiment, as used herein, the terms “increase”, increasing”“increased” may be used interchangeably and refer to an entity becomingprogressively greater (as in size, amount, number, or intensity),wherein for example the entity is sex hormone-binding globulin (SHBG) orprostate-specific antigen (PSA).

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing metastasis-free survival(MFS) in a subject suffering from non-metastatic prostate cancer. In oneembodiment, the non-metastatic prostate cancer is non-metastaticadvanced prostate cancer. In another embodiment, the non-metastaticprostate cancer is non-metastatic CRPC (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used to provide a dual action,for example treating prostate cancer and preventing metastases. In oneembodiment, the prostate cancer being treated is advanced prostatecancer. In one embodiment, the prostate cancer being treated iscastration resistant prostate cancer (CRPC). In one embodiment, theprostate cancer being treated is metastatic CRPC (mCRPC). In oneembodiment, the prostate cancer being treated is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC.

Men with advanced prostate cancer who are at high risk for progressionto castration resistant prostate cancer (CRPC), in one embodiment, aremen on ADT with serum total testosterone concentrations greater than 20ng/dL or in another embodiment, men with advanced prostate cancer who atthe time of starting ADT had either (1) confirmed Gleason pattern 4 or 5prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time<3 months, (4) a PSA ≧20 ng/mL, or (5) a PSA relapse in <3 years afterdefinitive local therapy (radical prostatectomy or radiation therapy).

Men with high risk non-metastatic castration resistant prostate cancer(high-risk nmCRPC) may include those with rapid PSA doubling times,having an expected progression-free survival of approximately 18 monthsor less (Miller K, Moul J W, Gleave M, et al. 2013. Phase III,randomized, placebo-controlled study of once-daily oral zibotentan(ZD4054) in patients with non-metastatic castration-resistant prostatecancer. Prostate Canc Prost Dis. February; 16:187-192). This relativelyrapid progression of their disease underscores the importance of noveltherapies for these individuals. In one embodiment, the PSA levels aregreater than 8 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the PSA doubling time is less than 8 months in a subjectsuffering from high-risk nmCRPC. In another embodiment, the PSA doublingtime is less than 10 months in a subject suffering from high-risknmCRPC. In one embodiment, the total serum testosterone levels aregreater than 20 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the serum free testosterone levels are greater thanthose observed in an orchidectomized male in a subject suffering fromhigh-risk nmCRPC.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with LHRH agonist orantagonist for increasing the progression free survival or overallsurvival of a subject suffering from prostate cancer. In anotherembodiment, the prostate cancer is advanced prostate cancer. In anotherembodiment, the prostate cancer is castration resistant prostate cancer(CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). Inanother embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, thesubject is surgically castrated. In another embodiment, the subject ischemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-programmeddeath receptor 1 (anti-PD-1) drugs (e.g., AMP-224, nivolumab,pembrolizumab, pidilizumab, AMP-554, and the like) for increasing theprogression free survival or overall survival of a subject sufferingfrom prostate cancer. In another embodiment, the prostate cancer isadvanced prostate cancer. In another embodiment, the prostate cancer iscastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject is surgically castrated. Inanother embodiment, the subject is chemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-PD-L1 drugs(e.g., BMS-936559, MEDI4736, MPDL3280A, MEDI4736, MSB0010718C, and thelike) for increasing the progression free survival or overall survivalof a subject suffering from prostate cancer. In another embodiment, theprostate cancer is advanced prostate cancer. In another embodiment, theprostate cancer is castration resistant prostate cancer (CRPC). Inanother embodiment, the CRPC is metastatic CRPC (mCRPC). In anotherembodiment, the CRPC is non-metastatic CRPC (nmCRPC). In one embodiment,the nmCRPC is high-risk nmCRPC. In another embodiment, the subject issurgically castrated. In another embodiment, the subject is chemicallycastrated.

In certain embodiments, treatment of prostate cancer, advanced prostatecancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningfulimprovement in prostate cancer related symptoms, function and/orsurvival. Clinically meaningful improvements include but are not limitedto increasing radiographic progression free survival (rPFS) if cancer ismetastatic, and increasing metastasis-free survival (MFS) if cancer isnon-metastatic.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing the survival of men withcastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject further receives androgendeprivation therapy.

In one embodiment, levels of prostate specific antigen (PSA) considerednormal are age dependent. In one embodiment, levels of prostate specificantigen (PSA) considered normal are dependent on the size of a malesubject's prostate. In one embodiment, PSA levels in the range between2.5-10 ng/mL are considered “borderline high”. In another embodiment,PSA levels above 10 ng/mL are considered “high”.

In one embodiment, the rate of change or “PSA velocity” is high. In oneembodiment, a rate of change or “PSA velocity” greater than 0.75/year isconsidered high.

In one embodiment, this invention provides a method of lowering serumprostate specific antigen (PSA) levels in a male subject suffering fromprostate cancer, advanced prostate cancer, metastatic prostate cancer orcastration resistant prostate cancer (CRPC), comprising administering atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by thestructure of formula I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVor XV or any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93,100-115, 130-137, or 200-205. In one embodiment, this invention isdirected to treatment of a subject with high or increasing PSA levelscomprising administering a SARD compound of this invention. In oneembodiment, this invention is directed to treatment of a subject withhigh or increasing PSA levels despite ongoing ADT or a history of ADT,surgical castration or despite treatment with antiandrogens and/or LHRHagonist. In another embodiment, the treatment makes use of compounds offormula I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV or anyone of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137,or 200-205.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas I-III, IXa,XIa, XIIIa or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is compound 11. In anotherembodiment, the compound is compound 11R. In another embodiment, thecompound is compound 12. In another embodiment, the compound is compound13. In another embodiment, the compound is compound 14. In anotherembodiment, the compound is compound 15. In another embodiment, thecompound is compound 16. In another embodiment, the compound is compound17. In another embodiment, the compound is compound 18. In anotherembodiment, the compound is compound 19. In another embodiment, thecompound is compound 20. In another embodiment, the compound is compound21. In another embodiment, the compound is compound 22. In anotherembodiment, the compound is compound 23. In another embodiment, thecompound is compound 24. In another embodiment, the compound is compound25. In another embodiment, the compound is compound 26. In anotherembodiment, the compound is compound 27. In another embodiment, thecompound is compound 30. In another embodiment, the compound is compound31. In another embodiment, the compound is compound 32. In anotherembodiment, the compound is compound 33. In another embodiment, thecompound is compound 34. In another embodiment, the compound is compound35. In another embodiment, the compound is compound 36. In anotherembodiment, the compound is compound 37. In another embodiment, thecompound is compound 38. In another embodiment, the compound is compound39. In another embodiment, the compound is compound 40. In anotherembodiment, the compound is compound 41. In another embodiment, thecompound is compound 42. In another embodiment, the compound is compound70. In another embodiment, the compound is compound 71. In anotherembodiment, the compound is compound 72. In another embodiment, thecompound is compound 73. In another embodiment, the compound is compound74. In another embodiment, the compound is compound 75. In anotherembodiment, the compound is compound 80. In another embodiment, thecompound is compound 90. In another embodiment, the compound is compound91. In another embodiment, the compound is compound 92. In anotherembodiment, the compound is compound 93.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas II, IV-VIII,IXb-IXd, X, XIb-XId, XII, XIIIb-XIIId or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is compound100. In another embodiment, the compound is compound 101. In anotherembodiment, the compound is compound 102. In another embodiment, thecompound is compound 103. In another embodiment, the compound iscompound 104. In another embodiment, the compound is compound 105. Inanother embodiment, the compound is compound 106. In another embodiment,the compound is compound 107. In another embodiment, the compound iscompound 108. In another embodiment, the compound is compound 109. Inanother embodiment, the compound is compound 110. In another embodiment,the compound is compound 111. In another embodiment, the compound iscompound 112. In another embodiment, the compound is compound 113. Inanother embodiment, the compound is compound 114. In another embodiment,the compound is compound 115. In another embodiment, the compound iscompound 130. In another embodiment, the compound is compound 131. Inanother embodiment, the compound is compound 132. In another embodiment,the compound is compound 133. In another embodiment, the compound iscompound 134. In another embodiment, the compound is compound 135. Inanother embodiment, the compound is compound 136. In another embodiment,the compound is compound 137.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas XIV or XV orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is compound 200. In another embodiment, the compound iscompound 201. In another embodiment, the compound is compound 202. Inanother embodiment, the compound is compound 203. In another embodiment,the compound is compound 204. In another embodiment, the compound iscompound 205.

In one embodiment, this invention provides a method of secondaryhormonal therapy that reduces serum PSA in a male subject suffering fromcastration resistant prostate cancer (CRPC) comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, thecastration is surgical castration.

In another embodiment, with regards to the methods described above, theprostate cancer depends on AR-FL and/or AR-SV for proliferation. Inanother embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, flutamide, bicalutamide,abiraterone, ARN-509, AZD-3514, galeterone, ASC-J9, flutamide,hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole,spironolactone, or any combination thereof. In another embodiment,administration of the compounds of formulas I-VIII, IXa-IXd, X, XIa-XId,XII, XIIIa-XIIId, XIV or XV, reduces the levels of AR, AR-full length(AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations,AR-splice variant (AR-SV), gene-amplified AR, or any combinationthereof, in the subject. In another embodiment, the castration issurgical castration. In another embodiment, the castration is chemicalcastration. In another embodiment, the CRPC is metastatic CRPC (mCRPC).In another embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, themethod further increases radiographic progression free survival (rPFS)in a subject suffering from a metastatic cancer. In another embodiment,the method further increases metastasis-free survival (MFS) in a subjectsuffering from non-metastatic cancer. In one embodiment, the method maybe used to provide a dual action, for example treating prostate cancerand preventing metastases. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject further receives LHRH agonist or antagonist. Inanother embodiment, the LHRH agonist is leuprolide acetate. In anotherembodiment, the subject had undergone orchidectomy. In anotherembodiment, the subject has high or increasing prostate specific antigen(PSA) levels. In another embodiment, the subject is a prostate cancerpatient. In another embodiment, the subject is a prostate cancer patienton ADT. In another embodiment, the subject is a prostate cancer patienton ADT with castrate levels of total T. In another embodiment, thesubject is an advanced prostate cancer patient. In another embodiment,the subject is an advanced prostate cancer patient on ADT. In anotherembodiment, the subject is an advanced prostate cancer patient on ADTwith castrate levels of total T. In another embodiment, the subject is aCRPC patient. In another embodiment, the subject is a CRPC patient onADT. In another embodiment, the subject is a CRPC patient on ADT withcastrate levels of total T. In another embodiment, the subject is ametastatic castration resistant prostate cancer (mCRPC) patient. Inanother embodiment, the subject is a mCRPC patient maintained on ADT. Inanother embodiment, the subject is a mCRPC patient maintained on ADTwith castrate levels of total T. In another embodiment, the subject is anon-metastatic castration resistant prostate cancer (nmCRPC) patient. Inanother embodiment, the subject is an nmCRPC patient maintained on ADT.In another embodiment, the subject is an nmCRPC patient maintained onADT with castrate levels of total T. In one embodiment, the nmCRPC ishigh-risk nmCRPC. In another embodiment, the method further treats,suppresses, reduces the incidence, reduces the severity, or inhibitsadvanced prostate cancer. In another embodiment, the method furtherprovides palliative treatment of advanced prostate cancer.

In one embodiment, this invention is directed to a method of reducingthe levels of AR, AR-full length, AR-FL with antiandrogenresistance-conferring AR-LBD mutations, and/or AR-splice variants in asubject, comprising administering to said subject a therapeuticallyeffective amount of a SARD compound according to this invention, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the reduction is achieved by degradation of said AR, AR-full length(AR-FL) and/or AR-splice variants (AR-SV). In another embodiment, thereduction is achieved by inhibition of said AR, AR-full length (AR-FL)and/or AR-splice variants (AR-SV). In another embodiment, the reductionis achieved by dual AR-SV/AR-FL degradation and AR-SV/AR-FL inhibitoryfunctions.

In one embodiment, this invention is directed to a method of reducingthe levels of AR-splice variants in a subject, comprising administeringto said subject a therapeutically effective amount of a SARD compoundaccording to this invention, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the method further reduces the levels ofAR-full length (AR-FL) in the subject. In another embodiment, thereduction is achieved by degradation of said AR-splice variants (AR-SV).In another embodiment, the reduction is further achieved by degradationof said AR-FL. In another embodiment, the reduction is achieved byinhibition of said AR-splice variants (AR-SV). In another embodiment,the reduction is further achieved by inhibition of said AR-FL. Inanother embodiment, the reduction is achieved by dual AR-SV degradationand AR-SV inhibitory functions. In another embodiment, the reduction isachieved by dual AR-FL degradation and AR-FL inhibitory functions.

In one embodiment, “a subject suffering from castration resistantprostate cancer” refers to a subject which has been previously treatedwith androgen deprivation therapy (ADT), has responded to the ADT andcurrently has a serum PSA >2 ng/mL or >2 ng/mL and representing a 25%increase above the nadir achieved on the ADT. In another embodiment, theterm refers to a subject which despite being maintained on androgendeprivation therapy is diagnosed to have serum PSA progression. Inanother embodiment, the subject has a castrate level of serum totaltestosterone (<50 ng/dL). In another embodiment, the subject has acastrate level of serum total testosterone (<20 ng/dL). In anotherembodiment, the subject has rising serum PSA on two successiveassessments at least 2 weeks apart. In another embodiment, the subjecthad been effectively treated with ADT. In another embodiment, thesubject has a history of serum PSA response after initiation of ADT. Inanother embodiment, the subject has been treated with ADT and had aninitial serum PSA response, but now has a serum PSA >2 ng/mL and a 25%increase above the nadir observed on ADT. In one embodiment, the CRPC ismetastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC.

The term “serum PSA response” refers to, in one embodiment, at least 90%reduction in serum PSA value prior to the initiation of ADT, to <10ng/mL or undetectable level of serum PSA (<0.2 ng/mL) at any time, or inanother embodiment to at least 50% decline from baseline in serum PSA,or in another embodiment to at least 90% decline from baseline in serumPSA, or in another embodiment to at least 30% decline from baseline inserum PSA, or in another embodiment to at least 10% decline frombaseline in serum PSA.

The term “serum PSA progression” refers to in one embodiment, a 25% orgreater increase in serum PSA and an absolute increase of 2 ng/ml ormore from the nadir; or in another embodiment, to serum PSA >2 ng/mL,or >2 ng/mL and a 25% increase above the nadir after the initiation ofandrogen deprivation therapy (ADT).

In another embodiment, the term “nadir” refers to the lowest PSA levelwhile a patient is undergoing ADT.

Testosterone can be measured as “free” (that is, bioavailable andunbound) or as “total” (including the percentage which is protein boundand unavailable) serum levels. In one embodiment, total serumtestosterone comprises free testosterone and bound testosterone.

The methods of this invention comprise administering a combination offorms of ADT and a compound of this invention. In one embodiment, formsof ADT include a LHRH agonist. In another embodiment, the LHRH agonistincludes leuprolide acetate (Lupron®)(U.S. Pat. No. 5,480,656; U.S. Pat.Nos. 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976which are all incorporated by reference herein) or goserelin acetate(Zoladex®) (U.S. Pat. Nos. 7,118,552; 7,220,247; 7,500,964 which are allincorporated by reference herein). In one embodiment, forms of ADTinclude an LHRH antagonist. In another embodiment, the LHRH antagonistincludes degarelix. In another embodiment, the LHRH antagonist includesabarelix. In one embodiment, forms of ADT include reversibleantiandrogens. In another embodiment, the antiandrogens includebicalutamide, flutamide, finasteride, dutasteride, enzalutamide,nilutamide, chlormadinone, abiraterone or any combination thereof. Inone embodiment, forms of ADT include bilateral orchidectomy.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a combination of one or more formsof ADT and a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV, XV or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the subject has failed androgen deprivationtherapy (ADT).

In one embodiment, this invention provides a method of lowering serumPSA levels in a male subject suffering from castration resistantprostate cancer (CRPC) comprising administering a therapeuticallyeffective amount of a combination of one or more forms of ADT and acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV,XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of an antiandrogen and a compound ofthis invention. In one embodiment, the methods of this inventioncomprise administering a therapeutically effective amount of an LHRHagonist and a compound of this invention. In one embodiment, the methodsof this invention comprise administering a therapeutically effectiveamount of an antiandrogen, LHRH agonist and a compound of thisinvention. In another embodiment, the compound is compound of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of an lyase inhibitor (e.g.,abiraterone) and a compound of this invention. In another embodiment,the compound is a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV or XV. In another embodiment, the compound is any oneof compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or200-205.

In another embodiment, this invention provides a method for androgendeprivation therapy (ADT) in a subject, comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, said subjecthas prostate cancer. In another embodiment, the prostate cancer iscastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In one embodiment, the CRPC isnon-metastatic castration resistant prostate cancer (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, thecompound is any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93,100-115, 130-137, or 200-205. In another embodiment, the subject hasfailed androgen deprivation therapy (ADT). In another embodiment, thesubject further receives androgen deprivation therapy (ADT).

In one embodiment, this invention provides a method of treating prostatecancer or delaying the progression of prostate cancer comprisingadministering a SARD compound of this invention. In one embodiment, thisinvention provides a method of preventing and/or treating the recurrenceof prostate cancer comprising administering a SARD compound of thisinvention. In another embodiment, the prostate cancer is castrationresistant prostate cancer (CRPC). In another embodiment, the CRPC ismetastatic CRPC (mCRPC). In one embodiment, the CRPC is non-metastaticcastration resistant prostate cancer (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, this invention provides a method of increasing thesurvival of a subject having prostate cancer, advanced prostate cancer,castration resistant prostate cancer or metastatic castration resistantprostate cancer or non-metastatic castration resistant prostate canceror high-risk non metastatic castration resistant prostate cancer,comprising administering a compound of this invention. In anotherembodiment, administering a compound of this invention in combinationwith LHRH analogs, reversible antiandrogens (such as bicalutamide,flutamide, or enzalutamide), anti-estrogens, estrogens (such asestradiol, ethinyl estradiol, or capesaris), anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, selectiveandrogen receptor modulators (SARMs) or agents acting through othernuclear hormone receptors. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In one embodiment, the compound is acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIVor XV. In another embodiment, the compound is any one of compounds11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or 200-205.

The term “advanced prostate cancer” refers to metastatic cancer havingoriginated in the prostate, and having widely metastasized to beyond theprostate such as the surrounding tissues to include the seminal vesiclesthe pelvic lymph nodes or bone, or to other parts of the body. Prostatecancer pathologies are graded with a Gleason grading from 1 to 5 inorder of increasing malignancy. In another embodiment, patients withsignificant risk of progressive disease and/or death from prostatecancer should be included in the definition and that any patient withcancer outside the prostate capsule with disease stages as low as IIBclearly has “advanced” disease. In another embodiment, “advancedprostate cancer” can refer to locally advanced prostate cancer.

Men with advanced prostate cancer often receive treatment to block theproduction of androgens, which are male sex hormones that may helpprostate tumors grow. However, prostate cancers that initially respondto antiandrogen therapy eventually develop the ability to grow withoutandrogens. Such cancers are often referred to as hormone refractory,androgen independent, or castration resistant.

In one embodiment, the advanced prostate cancer is castration resistantprostate cancer.

The term “castration resistant prostate cancer” (CRPC) refers toadvanced prostate cancer that is worsening or progressing while thepatient remains on ADT or other therapies to reduce testosterone, orprostate cancer which is considered hormone refractory, hormone naïve,androgen independent or chemical or surgical castration resistant. Inanother embodiment, CRPC is a result of AR activation by intracrineandrogen synthesis. In another embodiment, CRPC is a result ofexpression of AR splice variants (AR-SV) that lack ligand binding domain(LBD). In another embodiment, CRPC is a result of expression of AR-LBDmutations with potential to resist antagonists. In another embodiment,castration resistant prostate cancer (CRPC) is an advanced prostatecancer which developed despite ongoing ADT and/or surgical castration.In one embodiment, castration resistant prostate cancer is defined asprostate cancer that continues to progress or worsen or adversely affectthe health of the patient despite prior surgical castration, continuedtreatment with gonadotropin releasing hormone agonists (e.g.,leuprolide) or antagonists (e.g., degarelix), antiandrogens (e.g.,bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide),chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel,adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinaseinhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib(Cometriq™, also known as XL184)) or other prostate cancer therapies(e.g., vaccines (sipuleucel-T (Provenge®), GVAX, etc.), herbal (PC-SPES)and lyase inhibitor (abiraterone)) as evidenced by increasing or higherserum levels of prostate specific antigen (PSA), metastasis, bonemetastasis, pain, lymph node involvement, increasing size or serummarkers for tumor growth, worsening diagnostic markers of prognosis, orpatient condition.

In one embodiment, castration resistant prostate cancer is defined ashormone naïve prostate cancer.

Many early prostate cancers require androgens for growth, but advancedprostate cancers are in some embodiments, androgen-independent, orhormone naïve. In one embodiment, in men with castration resistantprostate cancer, the tumor cells may have the ability to grow in theabsence of androgens (hormones that promote the development andmaintenance of male sex characteristics).

In one embodiment, the term “androgen deprivation therapy” (ADT) or“traditional androgen deprivation therapy” is directed to orchidectomy(surgical castration) wherein the surgeon removes the testicles. Inanother embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administeringluteinizing hormone-releasing hormone (LHRH) analogs: these drugs lowerthe amount of testosterone made by the testicles. Examples of LHRHanalogs available in the United States include leuprolide (Lupron®,Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), andhistrelin (Vantas®). In another embodiment, the term “androgendeprivation therapy” or “traditional androgen deprivation therapy” isdirected to administering antiandrogens: Anti-androgens block the body'sability to use any androgens. Even after orchidectomy or duringtreatment with LHRH analogs, a small amount of androgens is still madeby the adrenal glands. Examples of antiandrogens drugs includeenzalutamide (Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®),and nilutamide (Nilandron®). In another embodiment, the term “androgendeprivation therapy” or “traditional androgen deprivation therapy” isdirected to administering luteinizing hormone-releasing hormone (LHRH)antagonists such as abarelix (Plenaxis®) or degarelix (Firmagon®)(approved for use by the FDA in 2008 to treat advanced prostate cancer).In another embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administering5α-reductase inhibitors such as finasteride (Proscar®) and dutasteride(Avodart®): 5α-reductase inhibitors block the body's ability to converttestosterone to the more active androgen, 5α-dihydrotestosterone (DHT).In another embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administeringinhibitors of testosterone biosynthesis such as ketoconazole (Nizoral®).In another embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administeringestrogens such as diethylstilbestrol, ethinyl estradiol, capesaris, or17β-estradiol. In another embodiment, the term “androgen deprivationtherapy” or “traditional androgen deprivation therapy” is directed toadministering 17α-hydroxylase/C17,20 lyase (CYP17A1) inhibitors such asabiraterone (Zytiga®).

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an antiandrogen-resistant prostate cancer.In another embodiment, the antiandrogen is bicalutamide,hydroxyflutamide, flutamide, or enzalutamide.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an abiraterone-resistant prostate cancer.

In one embodiment, the terms “treating” or “treatment” includespreventative as well as disorder remitative treatment. The terms“reducing”, “suppressing” and “inhibiting” have their commonlyunderstood meaning of lessening or decreasing, in another embodiment, ordelaying, in another embodiment, or reducing, in another embodiment, theincidence, severity or pathogenesis of a disease, disorder or condition.In embodiment, the term treatment refers to delayed progression of,prolonged remission of, reduced incidence of, or amelioration ofsymptoms associated with the disease, disorder or condition. In oneembodiment, the terms “treating” “reducing”, “suppressing” or“inhibiting” refer to a reduction in morbidity, mortality, or acombination thereof, in association with the indicated disease, disorderor condition. In one embodiment, the term “progression” refers to anincreasing in scope or severity, advancing, growing or becoming worse.The term “recurrence” means, in another embodiment, the return of adisease after a remission. In one embodiment, the methods of treatmentof the invention reduce the severity of the disease, or in anotherembodiment, symptoms associated with the disease, or in anotherembodiment, reduces the levels of biomarkers expressed during disease.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, post-polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in late adolescence to adulthood. Proximal limb and bulbarmuscle weakness results in physical limitations including dependence ona wheelchair in some cases. The mutation results in an extendedpolyglutamine tract at the N-terminal domain of the androgen receptor(polyQ AR). Binding and activation of the polyQ AR by endogeneousandrogens (testosterone and DHT) results in unfolding and nucleartranslocation of the mutant androgen receptor. These steps are requiredfor pathogenesis and results in partial loss of transactivation function(i.e., an androgen insensitivity) and a poorly understood neuromusculardegeneration. Currently there are no disease-modifying treatments butrather only symptom directed treatments. Efforts to target the polyQ ARas the proximal mediator of toxicity by harnessing cellular machinery topromote its degradation hold promise for therapeutic invention.Selective androgen receptor degraders such as those reported herein bindto and degrade a variety of androgen receptors (full length, splicevariant, antiandrogen resistance mutants, etc.), indicating that theyare promising leads for treatment of SBMA. This view is supported by theobservation that peripheral polyQ AR anti-sense therapy rescues diseasein mouse models of SBMA (Cell Reports 7, 774-784, May 8, 2014).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of the Kennedy's disease comprisingadministering therapeutically effective amount of a compound of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

As used herein, “androgen receptor associated conditions” or “androgensensitive diseases or disorders” are conditions, diseases, or disordersthat are modulated by or whose pathogenesis is dependent upon theactivity of the androgen receptor. The androgen receptor is expressed inmost tissues of the body however it is overexpressed in, inter alia, theprostate and skin. ADT has been the mainstay of prostate cancertreatment for many years, and a SARD may also be useful also in treatingvarious prostate cancers, benign prostatic hypertrophy, prostamegaly,and other maladies of the prostate.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of benign prostatic hypertrophy comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostamegaly comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperproliferative prostatic disorders anddiseases comprising administering a therapeutically effective amount ofa compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV, XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205.

The effect of the AR on the skin is apparent in the gender dimorphismand puberty related dermatological problems common to teens and earlyadults. The hyperandrogenism of puberty stimulates terminal hair growth,sebum production, and predisposes male teens to acne, acne vulgaris,seborrhea, excess sebum, hidradenitis suppurativa, hirsutism,hypertrichosis, hyperpilosity, androgenic alopecia, male patternbaldness, and other dermatological maladies. Although antiandrogenstheoretically should prevent the hyperandrogenic dermatological diseasesdiscussed, they are limited by toxicities, sexual side effects, and lackof efficacy when topically applied. The SARDs of this invention potentlyinhibit ligand-dependent and ligand-independent AR activation, and haveshort biological half-lives in the serum, suggesting that topicallyformulated SARDs of this invention could be applied to the areasaffected by acne, seborrheic dermatitis, and/or hirsutism without riskof systemic side effects.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne vulgaris comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrhea comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrheic dermatitis comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hidradenitis supporativa comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hirsutism comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hypertrichosis comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperpilosity comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of alopecia comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In some embodiments, the compounds as described herein and/orcompositions may be used for applications in or treating hair loss,alopecia, androgenic alopecia, alopecia areata, alopecia secondary tochemotherapy, alopecia secondary to radiation therapy, alopecia inducedby scarring or alopecia induced by stress. In one embodiment, “hairloss”, or “alopecia”, refers to baldness as in the very common type ofmale-pattern baldness. Baldness typically begins with patch hair loss onthe scalp and sometimes progresses to complete baldness and even loss ofbody hair. Hair loss affects both males and females.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgenic alopecia comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

SARDs of this invention may also be useful in the treatment of hormonalconditions in females such as precocious puberty, early puberty,dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis,hysteromyoma, abnormal uterine bleeding, early menarche, fibrocysticbreast disease, fibroids of the uterus, ovarian cysts, polycystic ovarysyndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor,premenstrual syndrome, and vaginal dryness.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of any hyper-androgenic diseases (for examplepolycystic ovary syndrome (PCOS)) comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precocious puberty or early pubertycomprising administering a therapeutically effective amount of acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV,XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of dysmenorrhea or amenorrhea comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of multilocular uterus syndrome,endometriosis, hysteromyoma, or abnormal uterine bleeding comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of fibrocystic breast disease, fibroids ofthe uterus, ovarian cysts, or polycystic ovary syndrome comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, or vaginal dryness comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

SARDS of this invention may also find utility in treatment of sexualperversion, hypersexuality, paraphilias, androgen psychosis,virilization, androgen insensitivity syndromes (AIS) such as completeAIS (CAIS) and partial AIS (PAIS), and improving ovulation in an animal.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of sexual perversion, hypersexuality, orparaphilias comprising administering a therapeutically effective amountof a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV, XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of virilization comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndromescomprising administering a therapeutically effective amount of acompound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV,XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205. In one embodiment, theandrogen insensitivity syndrome is a complete androgen insensitivitysyndrome. In another embodiment, the androgen insensitivity syndrome isa partial androgen insensitivity syndrome.

In one embodiment, this invention is directed to a method of increasing,modulating, or improving ovulation in an animal comprising administeringa therapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

SARDs of this invention may also be useful for the treating ofhormone-dependent cancers such as prostate cancer, breast cancer,testicular cancer, ovarian cancer, and urogenital cancer, etc. Further,local or systemic SARD administration may be useful for treatment ofprecursors of hormone dependent cancers such as prostaticintraepithelial neoplasia (PIN) and atypical small acinar proliferation(ASAP).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR related solid tumors. In anotherembodiment, the tumor is hepatocellular carcinoma. In anotherembodiment, the tumor is bladder cancer. Serum testosterone may bepositively linked to the development of HCC. Based on epidemiologic,experimental observations, and notably the fact that men have asubstantially higher risk of bladder cancer than women, androgens and/orthe AR also play a role in bladder cancer initiation.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of breast cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of testicular cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of ovarian cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of urogenital cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precursors of prostate cancer comprisinglocal or systemic administration of a therapeutically effective amountof a compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV, XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205. In one embodiment, theprecursor of prostate cancers is prostatic intraepithelial neoplasia(PIN). In another embodiment, the precursor of prostate cancer isatypical small acinar proliferation (ASAP).

SARD of this invention may also be useful for the treating other cancerscontaining AR such as breast, brain, skin, ovarian, bladder, lymphoma,liver, kidney, pancreas, endometrium, lung (e.g., NSCLC) colon, perianaladenoma, osteosarcoma, CNS, melanoma, etc.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of brain cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of skin cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of ovarian cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of bladder cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lymphoma comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of liver cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of renal cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of osteosarcoma comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pancreatic cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205. In one embodiment, this invention is directed to amethod of treating, suppressing, reducing the incidence, reducing theseverity, or inhibiting the progression of endometrial cancer comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lung cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, the lung cancer is non-small cell lung cancer(NSCLC).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a central nervous system cancer comprisingadministering a therapeutically effective amount of a compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of colon cancer comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of melanoma comprising administering atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering a therapeutically effective amount ofthe compound of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV, XV or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 11-27, 30-42, 11R,70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering a therapeutically effective amount of the compound offormulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, this invention provides a method of treating asubject suffering from a wound, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a woundin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205.

In one embodiment, this invention provides a method of treating asubject suffering from a burn, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a burnin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115,130-137, or 200-205. Wounds and/or ulcers are normally found protrudingfrom the skin or on a mucosal surface or as a result of an infarction inan organ. A wound may be a result of a soft tissue defect or a lesion orof an underlying condition. In one embodiment, the term “wound” denotesa bodily injury with disruption of the normal integrity of tissuestructures. The term is also intended to encompass the terms “sore”,“lesion”, “necrosis” and “ulcer”. In one embodiment, the term “sore”refers to any lesion of the skin or mucous membranes and the term“ulcer” refers to a local defect, or excavation, of the surface of anorgan or tissue, which is produced by the sloughing of necrotic tissue.Lesion generally relates to any tissue defect. Necrosis is related todead tissue resulting from infection, injury, inflammation orinfarctions. All of these are encompassed by the term “wound”, whichdenotes any wound at any particular stage in the healing processincluding the stage before any healing has initiated or even before aspecific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso: i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is as: i) small tissue loss due to surgicalincisions, minor abrasions and minor bites, or as ii) significant tissueloss. The latter group includes ischemic ulcers, pressure sores,fistulae, lacerations, severe bites, thermal burns and donor site wounds(in soft and hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

Since the skin is the most exposed part of the body, it is particularlysusceptible to various kinds of injuries such as, e.g., ruptures, cuts,abrasions, burns and frostbites or injuries arising from variousdiseases. Furthermore, much skin is often destroyed in accidents.However, due to the important barrier and physiologic function of theskin, the integrity of the skin is important to the well-being of theindividual, and any breach or rupture represents a threat that must bemet by the body in order to protect its continued existence.

Apart from injuries on the skin, injuries may also be present in allkinds of tissues (i.e. soft and hard tissues). Injuries on soft tissuesincluding mucosal membranes and/or skin are especially relevant inconnection with the present invention.

Healing of a wound on the skin or on a mucosal membrane undergoes aseries of stages that results either in repair or regeneration of theskin or mucosal membrane. In recent years, regeneration and repair havebeen distinguished as the two types of healing that may occur.Regeneration may be defined as a biological process whereby thearchitecture and function of lost tissue are completely renewed. Repair,on the other hand, is a biological process whereby continuity ofdisrupted tissue is restored by new tissues which do not replicate thestructure and function of the lost ones.

The majority of wounds heal through repair, meaning that the new tissueformed is structurally and chemically unlike the original tissue (scartissue). In the early stage of the tissue repair, one process which isalmost always involved is the formation of a transient connective tissuein the area of tissue injury. This process starts by formation of a newextracellular collagen matrix by fibroblasts. This new extracellularcollagen matrix is then the support for a connective tissue during thefinal healing process. The final healing is, in most tissues, a scarformation containing connective tissue. In tissues which haveregenerative properties, such as, e.g., skin and bone, the final healingincludes regeneration of the original tissue. This regenerated tissuehas frequently also some scar characteristics, e.g. a thickening of ahealed bone fracture.

Under normal circumstances, the body provides mechanisms for healinginjured skin or mucosa in order to restore the integrity of the skinbarrier or the mucosa. The repair process for even minor ruptures orwounds may take a period of time extending from hours and days to weeks.However, in ulceration, the healing can be very slow and the wound maypersist for an extended period of time, i.e. months or even years.

Burns are associated with reduced testosterone levels, and hypogonadismis associated with delayed wound healing. In one embodiment, the methodsof this invention, provide for treating a subject suffering from a woundor a burn via the administration of a SARD according to this invention.In one embodiment, the SARD promotes resolving of the burn or wound, orin another embodiment, participates in the healing process of a burn ora wound, or in another embodiment, treats a secondary complication of aburn or wound.

In one embodiment, the treatment of burns or wounds further incorporatesthe use of additional growth factors like epidermal growth factor (EGF),transforming growth factor-α (TGF-α), platelet derived growth factor(PDGF), fibroblast growth factors (FGFs) including acidic fibroblastgrowth factor (α-FGF) and basic fibroblast growth factor (β-FGF),transforming growth factor-β (TGF-β) and insulin like growth factors(IGF-1 and IGF-2), or any combination thereof, which are promoters ofwound healing.

Wound healing may be measured by many procedures known in the art,including wound tensile strength, hydroxyproline or collagen content,procollagen expression, and re-epithelialization. As an example, a SARDas described herein is administered orally or topically, at a dosage ofabout 0.1-1 mg per day. Therapeutic effectiveness is measured aseffectiveness in enhancing wound healing. Enhanced wound healing may bemeasured by known techniques such as decrease in healing time, increasein collagen density, increase in hydroxyproline, reduction incomplications, increase in tensile strength, and increased cellularityof scar tissue.

In one embodiment, the term “treating” and its included aspects, refersto the administration to a subject with the indicated disease, disorderor condition, or in some embodiments, to a subject predisposed to theindicated disease, disorder or condition. The term “predisposed to” isto be considered to refer to, inter alia, a genetic profile or familialrelationship which is associated with a trend or statistical increase inincidence, severity, etc. of the indicated disease. In some embodiments,the term “predisposed to” is to be considered to refer to inter alia, alifestyle which is associated with increased risk of the indicateddisease. In some embodiments, the term “predisposed to” is to beconsidered to refer to inter alia, the presence of biomarkers which areassociated with the indicated disease, for example, in cancer, the term“predisposed to” the cancer may comprise the presence of precancerousprecursors for the indicated cancer.

In some embodiments, the term “reducing the pathogenesis” is to beunderstood to encompass reducing tissue damage, or organ damageassociated with a particular disease, disorder or condition. In anotherembodiment, the term “reducing the pathogenesis” is to be understood toencompass reducing the incidence or severity of an associated disease,disorder or condition, with that in question. In another embodiment, theterm “reducing the pathogenesis” is to be understood to encompassreducing the number of associated diseases, disorders or conditions withthe indicated, or symptoms associated thereto.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of thisinvention, together with a pharmaceutically acceptable carrier ordiluent. A “therapeutically effective amount” as used herein refers tothat amount which provides a therapeutic effect for a given conditionand administration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a male subject. In one embodiment,the present invention encompasses administering the compounds of thepresent invention to a female subject.

This invention provides, in other embodiments, pharmaceutical productsof the compounds described herein. The term “pharmaceutical product”refers, in other embodiments, to a composition suitable forpharmaceutical use (pharmaceutical composition), for example, asdescribed herein.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV, XV or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof containing, for example, one or morepharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

The mode of administration and dosage form are closely related to thetherapeutic amounts of the compounds or compositions which are desirableand efficacious for the given treatment application.

The pharmaceutical compositions containing a compound of this inventioncan be administered to a subject by any method known to a person skilledin the art, such as orally, parenterally, intravascularly,paracancerally, transmucosally, transdermally, intramuscularly,intranasally, intravenously, intradermally, subcutaneously,sublingually, intraperitoneally, intraventricularly, intracranially,intravaginally, by inhalation, rectally, intratumorally, or by any meansin which the composition can be delivered to tissue (e.g., needle orcatheter). Alternatively, topical administration may be desired forapplication to the dermal, ocular or mucosal surfaces. Another method ofadministration is via aspiration or aerosol formulation. Further, inanother embodiment, the pharmaceutical compositions may be administeredtopically to body surfaces, and are thus formulated in a form suitablefor topical administration. Suitable topical formulations include gels,ointments, creams, lotions, drops and the like. For topicaladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like areprepared and applied as solutions, suspensions, or emulsions in aphysiologically acceptable diluent with or without a pharmaceuticalcarrier.

Suitable dosage forms include but are not limited to oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterileadministration, and other dosage forms for systemic delivery of activeingredients. In some applications, formulations suitable for oraladministration are preferred. In some applications, formulationssuitable for topical administration are preferred.

Topical Administration:

In a typical embodiment, the compounds of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV or XV are administered topically. Topicaladministration is especially appropriate for hirsutism, alopecia, acneand excess sebum. The dose will vary, but as a general guideline, thecompound will be present in a dermatologically acceptable carrier in anamount of from about 0.01 to 50 w/w %, and more typically from about 0.1to 10 w/w %. Typically, the dermatological preparation will be appliedto the affected area from 1 to 4 times daily. “Dermatologicallyacceptable” refers to a carrier which may be applied to the skin orhair, and which will allows the drug to diffuse to the site of action.More specifically, it refers to a site where inhibition of androgenreceptor or degradation of androgen receptor is desired.

In a further embodiment, the compounds of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV or XV are used topically to relievealopecia, especially androgenic alopecia. Androgens have a profoundeffect on both hair growth and hair loss. In most body sites, such asthe beard and pubic skin, androgens stimulate hair growth by prolongingthe growth phase of the hair cycle (anagen) and increasing folliclesize. Hair growth on the scalp does not require androgens but,paradoxically, androgens are necessary for the balding on the scalp ingenetically predisposed individuals (androgenic alopecia) where there isa progressive decline in the duration of anagen and in hair folliclesize. Androgenic alopecia is also common in women where it usuallypresents as a diffuse hair loss rather than showing the patterning seenin men.

While the compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV or XV will most typically be used to alleviateandrogenic alopecia, the invention is not limited to this specificcondition. The compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV or XV may be used to alleviate any type of alopecia.Examples of non-androgenic alopecia include alopecia areata, alopeciadue to radiotherapy or chemotherapy, scarring alopecia, stress relatedalopecia, etc. As used in this application “alopecia” refers to partialor complete hair loss on the scalp.

Thus, the compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV or XV can be applied topically to the scalp and hair toprevent, or alleviate balding. Further, the compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV can be appliedtopically in order to induce or promote the growth or regrowth of hairon the scalp.

In a further embodiment of the invention, a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV is applied topically inorder to prevent the growth of hair in areas where such hair growth innot desired. One such use will be to alleviate hirsutism. Hirsutism isexcessive hair growth in areas that typically do not have hair (i.e., afemale face). Such inappropriate hair growth occurs most commonly inwomen and is frequently seen at menopause. The topical administration ofthe compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV or XV will alleviate this condition leading to a reduction, orelimination of this inappropriate, or undesired, hair growth.

The compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV or XV may also be used topically to decrease sebum production. Sebumis composed of triglycerides, wax esters, fatty acids, sterol esters andsqualene. Sebum is produced in the acinar cells of the sebaceous glandsand accumulates as these cells age. At maturation, the acinar cellslyse, relasing sebum into the luminal duct so that it may be depositedon the surface of the skin.

In some individuals, an excessive quantity of sebum is secreted onto theskin. This can have a number of adverse consequences. It can exacerbateacne, since sebum is the primary food source for Propionbacterium acnes,the causative agent of acne. It can cause the skin to have a greasyappearance, typically considered cosmetically unappealing.

Formation of sebum is regulated by growth factors and a variety ofhormones including androgens. The cellular and molecular mechanism bywhich androgens exert their influence on the sebaceous gland has notbeen fully elucidated. However, clinical experience documents the impactandrogens have on sebum production. Sebum production is significantlyincreased during puberty, when androgen levels are their highest. Thusthe compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV or XV inhibit the secretion of sebum and thus reduce the amount ofsebum on the surface of the skin. The compounds of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV can be used to treat avariety of dermal diseases such as acne or seborrheic dermatitis.

In addition to treating diseases associated with excess sebumproduction, the compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII,XIIIa-XIIId, XIV or XV can also be used to achieve a cosmetic effect.Some consumers believe that they are afflicted with overactive sebaceousglands. They feel that their skin is oily and thus unattractive. Theseindividuals can utilize the compounds of formulas I-VIII, IXa-IXd, X,XIa-XId, XII, XIIIa-XIIId, XIV or XV to decrease the amount of sebum ontheir skin. Decreasing the secretion of sebum will alleviate oily skinin individuals afflicted with such conditions.

The compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV or XV of this invention will typically be administered topically. Asused herein, topical refers to application of the compounds of formulasI-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV (and optionalcarrier) directly to the skin and/or hair. The topical compositionaccording to the present invention can be in the form of solutions,lotions, salves, creams, ointments, liposomes, sprays, gels, foams,roller sticks, and any other formulation routinely used in dermatology.

Thus, a further embodiment relates to cosmetic or pharmaceuticalcompositions, in particular dermatological compositions, which compriseat least one of the compounds corresponding to formulas I-VIII, IXa-IXd,X, XIa-XId, XII, XIIIa-XIIId, XIV or XV above. Such dermatologicalcompositions will contain from 0.001% to 10% w/w % of the compounds inadmixture with a dermatologically acceptable carrier, and moretypically, from 0.1 to 5 w/w % of the compounds. Such compositions willtypically be applied from 1 to 4 times daily. The reader's attention isdirected to Remington's Pharmaceutical Science, Edition 17, MarkPublishing Co., Easton, Pa. for a discussion of how to prepare suchformulations.

The compositions according to the invention can also consist of solidpreparations constituting cleansing soaps or bars. These compositionsare prepared according to the usual methods.

The compounds of formulas I-VIII, IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId,XIV or XV can also be used for the hair in the form of aqueous,alcoholic or aqueous-alcoholic solutions, or in the form of creams,gels, emulsions or mousses, or alternatively in the form of aerosolcompositions also comprising a propellant under pressure. Thecomposition according to the invention can also be a hair carecomposition, and in particular a shampoo, a hair-setting lotion, atreating lotion, a styling cream or gel, a dye composition, a lotion orgel for preventing hair loss, etc. The amounts of the variousconstituents in the dermatological compositions according to theinvention are those conventionally used in the fields considered.

The medicinal and cosmetics containing the compounds of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV will typically bepackaged for retail distribution (i.e., an article of manufacture). Sucharticles will be labeled and packaged in a manner to instruct thepatient how to use the product. Such instructions will include thecondition to be treated, duration of treatment, dosing schedule, etc.

Antiandrogens, such as finasteride or flutamide, have been shown todecrease androgen activity or block androgen action in the skin to someextent but suffer from undesirable systemic effects. An alternativeapproach is to topically apply a selective androgen receptor degrader(SARD) compound to the affected areas. In one embodiment, such a SARDcompound would exhibit potent but local inhibition of AR activity. Inanother embodiment, the SARD compound would exhibit potent but localdegradation of AR activity. In another embodiment, the SARD compoundwould not penetrate to the systemic circulation of the subject. Inanother embodiment, the SARD compound would be rapidly metabolized uponentry into the blood, limiting systemic exposure.

To prepare such pharmaceutical dosage forms, the active ingredient maybe mixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration.

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formuations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Oral or Parenteral Administration:

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. Due to their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit form. If desired,tablets may be sugar coated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients, for example, ingredients that aidsolubility or for preservation, may be included. Injectable solutionsmay also be prepared in which case appropriate stabilizing agents may beemployed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitablefor oral administration may be presented as discrete units such ascapsules, cachets, tablets, or lozenges, each containing a predeterminedamount of the active ingredient as, for example, a powder or granules.Optionally, a suspension in an aqueous liquor or a non-aqueous liquidmay be employed, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with, for example, a binder, disintegrant,lubricant, inert diluent, surface active agent, or discharging agent.Molded tablets comprised of a mixture of the powdered active compoundwith a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration may comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery. Administration may for example be intravenous, intra-arterial,intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal(e.g., intraperitoneal), etc., and may be effected by infusion pumps(external or implantable) or any other suitable means appropriate to thedesired administration modality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from, for example, diluents, buffers, flavoring agents,binders, disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

The formulations of the present invention can have immediate release,sustained release, delayed-onset release or any other release profileknown to one skilled in the art.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 1-3000 mg per day. In additional embodiments, a compound of thisinvention is administered at a dose of 1-10 mg per day, 3-26 mg per day,3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day,15-60 mg, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day,125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg perday, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day,1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day,2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of25 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 40 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 50 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of67.5 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 75 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 80 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of100 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 125 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 250 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 300 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of600 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 1000 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 1500 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 2000 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 2500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of3000 mg per day. In another embodiment, the compound is any one ofcompounds 11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or200-205.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 3 mg. In additional embodiments, a compound of this invention isadministered at a dosage of 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg,120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg,1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg. In another embodiment,the compound is any one of compounds 11-27, 30-42, 11R, 70-75, 80,90-93, 100-115, 130-137, or 200-205.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 0.1 mg/kg/day. In additional embodiments, a compound of thisinvention is administered at a dosage between 0.2 to 30 mg/kg/day, or0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.

In one embodiment, the methods of this invention provide for the use ofa pharmaceutical composition comprising a compound of formulas I-VIII,IXa-IXd, X, XIa-XId, XII, XIIIa-XIIId, XIV or XV or any one of compounds11-27, 30-42, 11R, 70-75, 80, 90-93, 100-115, 130-137, or 200-205.

In certain embodiment, the pharmaceutical composition is a solid dosageform. In another embodiment, the pharmaceutical composition is a tablet.In another embodiment, the pharmaceutical composition is a capsule. Inanother embodiment, the pharmaceutical composition is a solution. Inanother embodiment, the pharmaceutical composition is a transdermalpatch.

In one embodiment, use of a compound of this invention or a compositioncomprising the same, will have utility in inhibiting, suppressing,enhancing or stimulating a desired response in a subject, as will beunderstood by one skilled in the art. In another embodiment, thecompositions may further comprise additional active ingredients, whoseactivity is useful for the particular application for which the compoundof this invention is being administered.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight, genetics and/or response of the particularindividual.

In some embodiments, any of the compositions of this invention willcomprise a compound of this invention, in any form or embodiment asdescribed herein. In some embodiments, any of the compositions of thisinvention will consist of a compound of this invention, in any form orembodiment as described herein. In some embodiments, of the compositionsof this invention will consist essentially of a compound of thisinvention, in any form or embodiment as described herein. In someembodiments, the term “comprise” refers to the inclusion of theindicated active agent, such as the compound of this invention, as wellas inclusion of other active agents, and pharmaceutically acceptablecarriers, excipients, emollients, stabilizers, etc., as are known in thepharmaceutical industry. In some embodiments, the term “consistingessentially of” refers to a composition, whose only active ingredient isthe indicated active ingredient, however, other compounds may beincluded which are for stabilizing, preserving, etc. the formulation,but are not involved directly in the therapeutic effect of the indicatedactive ingredient. In some embodiments, the term “consisting essentiallyof” may refer to components which facilitate the release of the activeingredient. In some embodiments, the term “consisting” refers to acomposition, which contains the active ingredient and a pharmaceuticallyacceptable carrier or excipient.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention. In one embodiment, the compounds are a free base, free acid,non charged or non-complexed compound.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of Indole/Pyrrolo-Pyridine SARD Compoundsof this Invention

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)

D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath. The resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The temperature of the mixture was kept at 10-11° C. during the additionof the methacryloyl chloride. After stirring (3 h, room temperature(RT)), the mixture was evaporated in vacuo at a temperature at 35-45° C.to remove acetone. The resulting solution was washed with ethyl etherand was acidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite®, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (Marhefka, C. A.; Moore, B. M., 2nd; Bishop, T. C.; Kirkovsky, L.;Mukherjee, A.; Dalton, J. T.; Miller, D. D. Homology modeling usingmultiple molecular dynamics simulations and docking studies of the humanandrogen receptor ligand binding domain bound to testosterone andnonsteroidal ligands. J Med Chem 2001, 44, 1729-40: mp 102.5-103.5° C.);the NMR spectrum of this compound demonstrated the existence of tworotamers of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the secondrotamer (totally 2H for both rotamers, vinyl CH₂), 4.48-4.44 for thefirst rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for bothrotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12(1H, CH), 1.97-1.72 (m, 6H, CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δfor major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7,19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0,22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508,1459, 1369, 1348, 1178 cm⁻¹; [α]_(D) ²⁶ +80.8° (c=1, MeOH); Anal. Calcd.for C₉H₁₃NO₃: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N,7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the(2R)-1-methacryloylpyrrolidin-2-carboxylic acid (2) (16.1 g, 88 mmol) in70 mL of DMF under argon at RT, and the resulting mixture was stirred 3days. The solvent was removed in vacuo, and a yellow solid wasprecipitated. The solid was suspended in water, stirred overnight at RT,filtered, and dried to give 18.6 g (81%) (smaller weight when dried˜34%)of the titled bromolactone (3) as a yellow solid: mp 158.1-160.3° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4 Hz,1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72(m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474,1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹;[α]_(D) ²⁶ +124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C,41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N, 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4)

A mixture of bromolactone (3) (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite®, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.;¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d,J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500(COOH), 1730 (C═O), 1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH); Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86.Found: C, 26.28; H, 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4) (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere.The resulting mixture was stirred for 3 h under the same condition. Tothis was added Et₃N (39.14 g, 0.39 mol) and stirred for 20 min under thesame condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g,0.21 mol), 400 mL of THF were added and then the mixture was allowed tostir overnight at RT. The solvent was removed under reduced pressure togive a solid which was treated with 300 mL of H₂O, extracted with EtOAc(2×400 mL). The combined organic extracts were washed with saturatedNaHCO₃ solution (2×300 mL) and brine (300 mL). The organic layer wasdried over MgSO₄ and concentrated under reduced pressure to give a solidwhich was purified from column chromatography using CH₂Cl₂/EtOAc (80:20)to give a solid. This solid was recrystallized from CH₂Cl₂/hexane togive 55.8 g (73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8) as a light-yellow solid. M.p. 134.0-136.5° C.; ¹H NMR (CDCl₃/TMS) δ1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d, J=10.8 Hz, 1H, CH₂), 4.05(d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1,8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH).Calculated Mass: 349.99, [M−H]⁻ 349.0.

Structures of compounds synthesized with different substituents: (R)- or(S)—N-(4-cyano-3-(trifluoromethyl)-phenyl)-3-(Substituted-1H-indol-1-yl)-2-hydroxy-2-methylpropanamides(11-27, 11R, 30-32, and 80)

Compounds 11-27, 11R, 30-32, and 80 were prepared by the generalprocedures as shown in Scheme 1 or Scheme 2, or Example 2. 11R wassynthesized by same procedures as the other compounds but usingL-proline instead of D-proline as a starting material. And also, 19 wasisolated from the synthetic product of 11 as a by-product.

General Synthetic Procedure of Compounds 11-27, 11R, 30-32, and 80.

Step 1.

Preparation of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(10) in THF: A mixture of hydroxylbromide 8 (1.0 g, 2.84 mmol) andpotassium carbonate (790 mg, 5.70 mmol) in 60 mL acetone was heated toreflux for 30 min. After complete conversion of starting bromide 8 todesired epoxide 10 as monitored by TLC, the solvent was evaporated underreduced pressure to give yellowish residue, which was poured into 20 mLof anhydrous EtOAc. The solution was filtered through Celite® pad toremove K₂CO₃ residue and condensed under reduced pressure to give ayellowish solid of epoxide 10, which was dissolved in 5 mL of anhydrousTHF to prepare a solution of epoxide 10 in THF. The resulting solutionwas directly used as next reactant without analysis.

Step 2. NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) wasadded in 30 mL of anhydrous THF solvent into a 100 mL dried two neckedround bottom flask equipped with a dropping funnel and substitutedindole/pyrrolo-pyridine (2.84 mmol) was added to the solution underargon atmosphere in ice-water bath, and the resulting solution wasstirred for 30 min in an ice-water bath. Into the flask, the preparedsolution of epoxide 10 (2.84 mmol in THF) was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at RT. After adding 1 mL of H₂O (1N HCl in case for compound15), the reaction mixture was condensed under reduced pressure, and thendispersed into 50 mL of EtOAc, washed with 50 mL (×2) water, brine,dried over anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography as an eluent EtOAc/hexane, andthen the condensed compounds were then recrystallized in EtOAc/hexane togive any one of the target products 11-27, 11R, 30-32, and 80.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(11)

Yield 68%; White solid. MS (ESI): 404.0 [M−H]⁻; 428.2 [M+Na]⁺; mp147.5-148.9° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.77 (bs, 1H, NH), 7.90 (d,J=1.7 Hz, 1H), 7.78-7.76 (m, 2H), 7.38 (dd, J=9.0, 4.2 Hz, 1H), 7.23(dd, J=9.3, 2.5 Hz, 1H), 7.19 (d, J=3.2 Hz, 1H), 6.98 (dt, J=9.0, 2.5Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.38 (d,J=14.8 Hz, 1H), 2.49 (bs, 1H, OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-nitro-1H-indol-1-yl)propanamide(12)

Yield 41%; Yellowish solid; mp 152.9-154.8° C.; MS (ESI): 430.9 [M−H]⁻;¹H NMR (CDCl₃, 400 MHz) δ 8.88 (bs, 1H), 8.04 (d, J=1.6 Hz, 1H), 7.89(s, 1H), 7.79-7.75 (m, 3H), 7.31 (m, 1H), 7.26 (m, 2H), 4.69 (d, J=14.8Hz, 1H), 4.42 (d, J=14.8 Hz, 1H), 2.43 (bs, 1H, OH), 1.63 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-methyl-1H-indol-1-yl)propanamide(13)

Yield 59%; Yellowish solid: mp 148.6-150.2° C.; MS (ESI): 400.0 [M−H]⁻;424.2 [M+Na]⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.72 (bs, 1H), 7.86 (d, J=2.0Hz, 1H), 7.78 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 6.84 (dd, J=21.2, 3.2 Hz,1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.63 (d,J=14.8 Hz, 1H), 4.31 (d, J=14.8 Hz, 1H), 3.82 (s, 3H), 2.51 (s, 1H, OH),1.60 (s, 3H).

(S)-3-(5-Cyano-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(14)

Yield 54%; White solid: MS (ESI): 411.0 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz)δ 8.85 (bs, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.80-7.73 (m,2H), 7.53 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (m, 1H), 6.59(d, J=3.2 Hz, 1H), 4.68 (d, J=14.8 Hz, 1H), 4.40 (d, J=14.8 Hz, 1H),2.94 (bs, 1H, OH), 1.64 (s, 3H).

(S)-1-(3-((4-Cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-indole-3-carboxylicacid (15)

Yield 31%; Light yellowish solid: MS (ESI): 429.9 [M−H]⁻; ¹H NMR (CDCl₃,400 MHz) δ 9.10 (bs, 1H), 8.11 (m, 1H), 8.01 (s, 1H), 7.91 (m, 2H), 7.84(d, J=1.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.51-7.49 (m, 1H), 7.22-7.20 (m,1H), 4.62 (d, J=14.8 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 2.94 (s, 1H, OH),1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(5-methoxy-1H-indol-1-yl)-2-methylpropanamide(16)

Yield 53%; Brown solid: MS (ESI): 416.0 [M−H]⁻; 418.2 [M+H]⁺; 440.2[M+Na]⁺; ¹H NMR (CDCl₃, 400 MHz) δ 8.74 (bs, 1H), 7.87 (d, J=2.2 Hz,1H), 7.81-7.75 (m, 2H), 7.30 (d, J=3.2 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H),7.03 (d, J=2.2 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 4.63 (d, J=14.8 Hz, 1H),4.30 (d, J=14.8 Hz, 1H), 3.82 (s, 3H), 2.60 (bs, 1H, OH), 1.62 (s, 3H).

(S)-3-(5-Chloro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(17)

Yield 62%; White solid: MS (ESI): 420.0 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz)δ 8.85 (bs, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.78 (m, 2H), 7.62 (s, 1H),7.32 (d, J=3.2 Hz, 1H), 7.12 (m, 2H), 6.65 (d, J=3.2 Hz, 1H), 4.65 (d,J=14.8 Hz, 1H), 4.31 (d, J=14.8 Hz, 1H), 2.52 (bs, 1H, OH), 1.61 (s,3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-(trifluoromethyl)-1H-indol-1-yl)propanamide(18)

Yield 57%; White solid: MS (ESI): 453.9 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz)δ 8.80 (bs, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.75 (m, 2H), 7.51 (d, J=3.2Hz, 1H), 7.41 (m, 1H), 7.21 (m, 1H), 6.62 (d, J=3.2 Hz, 1H), 4.68 (d,J=14.8 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H), 2.49 (s, 1H, OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-((S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)-3-(5-fluoro-1H-indol-1-yl)-2-methylpropanamide(19)

White solid: MS (ESI): 673.9 [M−H]⁻; 698.2 [M+Na]⁺; ¹H NMR (CDCl₃, 400MHz) δ 9.14 (bs, 1H), 8.62 (bs, 1H), 8.16 (d, J=1.8 Hz, 1H), 8.06 (dd,J=8.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.75(d, J=8.8 Hz, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.45 (s, 1H), 7.35 (m,1H), 7.24 (m, 1H), 6.98 (d, J=3.2 Hz, 1H), 6.24 (d, J=3.2 Hz, 1H), 4.54(d, J=14.8 Hz, 1H), 4.36 (d, J=14.8 Hz, 1H), 3.96 (d, J=8.8 Hz, 1H),3.55 (d, J=8.8 Hz, 1H), 2.76 (s, 1H, OH), 1.69 (s, 3H), 1.38 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(5-nitro-1H-indol-1-yl)propanamide(20)

Yield 47%; Yellowish solid: MS (ESI): 431.0 [M−H]⁻; ¹H NMR (Acetone-d₆,400 MHz) δ 9.68 (bs, 1H, NH), 8.35 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 8.01(m, 1H), 7.88-7.81 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.38 (d, J=3.4 Hz,1H), 6.58 (d, J=3.4 Hz, 1H), 5.49 (s, 1H, OH), 4.66 (d, J=14.8 Hz, 1H),4.38 (d, J=14.8 Hz, 1H), 1.50 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(5-iodo-1H-indol-1-yl)-2-methylpropanamide(21)

Yield 48%; MS (ESI) 511.9 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.71 (bs,1H, NH), 7.91 (d, J=1.6 Hz, 1H), 7.74 (m, 2H), 7.43 (dd, J=8.8, 1.6 Hz,1H), 7.21 (d, J=8.8 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.44 (d, J=3.2 Hz,1H), 4.62 (d, J=15.0 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.44 (bs, 1H,OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(22)

Yield 48%; MS (ESI) 511.9 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ 8.71 (bs,1H, NH), 7.91 (d, J=1.6 Hz, 1H), 7.74 (m, 2H), 7.43 (dd, J=8.8, 1.6 Hz,1H), 7.21 (d, J=8.8 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.44 (d, J=3.2 Hz,1H), 4.62 (d, J=15.0 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.44 (bs, 1H,OH), 1.61 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(23)

Yield 48%; White solid; MS (ESI) 404.0 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ8.79 (bs, 1H, NH), 7.89 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.77(d, J=8.0 Hz, 1H), 7.51 (dd, J=8.4, 5.2 Hz, 1H), 7.14 (dd, J=10.0, 2.0Hz, 1H), 7.11 (d, J=3.2 Hz, 1H), 6.87 (dt, J=8.8, 2.0 Hz, 1H), 6.51 (d,J=3.2 Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.32 (d, J=14.8 Hz, 1H), 2.56(bs, 1H, OH), 1.65 (s, 3H).

(S)-3-(5-Bromo-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(24)

Yield; 71%; MS (ESI) 465.1 [M−H]⁻; ¹H NMR (CDCl₃, 400 MHz) d 8.73 (bs,1H, NH), 7.88 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H),7.30 (d, J=8.8 Hz, 1H), 7.24 (m, 1H), 7.24 (dd, J=8.8, 2.0 Hz, 1H), 7.13(d, J=3.2 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 4.39 (d, J=14.8 Hz, 1H), 2.60(bs, 1H, OH), 1.65 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(1H-indol-1-yl)-2-methylpropanamide(27)

Yield 55%; Light brown solid; MS (ESI) 358.9 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 8.67 (bs, 1H, NH), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (s, 1H),7.71-7.65 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.12(t, J=8.0 Hz, 1H), 7.02 (m, 1H), 6.45 (d, J=3.2 Hz, 1H), 4.58 (d, J=14.8Hz, 1H), 4.30 (d, J=14.8 Hz, 1H), 2.50 (bs, 1H, OH), 1.54 (s, 3H).

Preparation of 30 from 15:

(S)-Ethyl1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-indole-3-carboxylate(30)

To a solution of carboxylic acid 15 (200 mg, 0.46 mmol) in absoluteethanol of 10 mL was added dropwise a catalytic amount of c-H₂SO₄ underargon atmosphere. The solution was heated to reflux for 30 min andcooled down to room temperature. The solution was concentrated underreduced pressure and dispersed in EtOAc and then washed with water. Theresulting solution was dried over anhydrous Na₂SO₄ and purified withflash column chromatography as an eluent EtOAc/hexane (1/2, v/v) to givethe title compound.

Yield; 92%; MS (ESI) r/z 458.1 [M−H]⁻; 482.4 [M+Na]⁺; ¹H NMR (400 MHz,CDCl₃) δ 8.86 (bs, 1H, NH), 8.00 (m, 2H), 7.81 (s, 1H), 7.65 (s, 2H),7.46 (d, J=8.0 Hz, 1H), 7.24-7.18 (m, 2H), 4.65 (d, J=14.4 Hz, 1H), 4.39(d, J=14.4 Hz, 1H), 4.36 (bs, 1H, OH), 4.23-4.11 (m, 2H), 1.66 (s, 3H),1.35 (t, J=7.2 Hz, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(31)

Yield; 64%; MS (ESI) m/z 418.1 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 8.85(bs, 1H, NH), 7.86 (m, 1H), 7.81-7.74 (m, 2H), 7.29 (dd, J=9.0, 4.0 Hz,1H), 7.14 (dd, J=9.0, 2.4 Hz, 1H), 6.92 (m, 2H), 4.60 (d, J=15.2 Hz,1H), 4.27 (d, J=15.2 Hz, 1H), 2.22 (s, 3H), 1.57 (s, 3H).

(S)-3-(5-Cyano-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(80)

Yield; 67%; MS (ESI) r/z 412.1 [M−H]⁻; 436.1 [M+Na]⁺; ¹H NMR (400 MHz,acetone-d₆) δ 9.84 (bs, 1H, NH), 8.31 (s, 1H), 8.14 (m, 2H), 8.01 (m,1H), 7.81 (d, J=2.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.8 Hz,1H), 5.64 (bs, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.52 (d, J=14.8 Hz, 1H),1.66 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(6-nitro-1H-indol-1-yl)propanamide(32)

Yield; 31%; MS (ESI) m/z 431.1 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 8.87(bs, 1H, NH), 8.53 (m, 1H), 8.01 (dd, J=8.8, 2.0 Hz, 1H), 7.92 (d, J=2.0Hz, 1H), 7.86 (dd, J=8.4, 2.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.8 Hz, 1H), 7.43 (d, J=3.0 Hz, 1H), 6.61 (d, J=3.0 Hz, 1H), 4.76 (d,J=14.8 Hz, 1H), 4.48 (d, J=14.8 Hz, 1H), 3.14 (s, 1H, OH), 1.74 (s, 3H).

(R)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(11R)

11R was synthesized by the same procedures as the other compounds butusing L-proline instead of D-proline as a starting material.

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 20mL of anhydrous THF solvent into a 100 mL dried two necked round bottomflask equipped with a dropping funnel. 5-Fluoroindole (390 mg, 2.84mmol) was added to the solution under argon atmosphere in ice-waterbath, and the resulting solution was stirred for 30 min in an ice-waterbath. Into the flask, epoxide 10R (2.84 mmol in THF) was added through adropping funnel under argon atmosphere in an ice-water bath and stirredovernight at RT. After adding 1 mL of H₂O, the reaction mixture wascondensed under reduced pressure, and then dispersed into 50 mL ofEtOAc, washed with 50 mL (×2) water, brine, dried over anhydrous MgSO₄,and evaporated to dryness. The mixture was purified with flash columnchromatography as an eluent EtOAc/hexane, and then the condensedcompounds were then recrystallized in EtOAc/hexane to give a targetproduct 11R.

Yield 69%; White solid. MS (ESI): 404.1 [M−H]⁻; 428.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 8.69 (bs, 1H, NH), 7.80 (d, J=1.2 Hz, 1H), 7.71-7.66(m, 2H), 7.29-7.26 (m, 2H), 7.14 (dd, J=9.2, 2.4 Hz, 1H), 7.09 (d, J=3.2Hz, 1H), 6.86 (dt, J=9.0, 2.5 Hz, 1H), 6.39 (d, J=3.2 Hz, 1H), 4.56 (d,J=14.8 Hz, 1H), 4.26 (d, J=14.8 Hz, 1H), 2.51 (bs, 1H, OH), 1.54 (s,3H).

Example 2 Synthesis of Benzimidazole and Indazole SARD Compounds of thisInvention

(S)—N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(5-fluoro-benzoimidazol-1-yl)-2-hydroxy-2-methyl-propionamide(C₁₉H₁₄F₄N₄O₂) (70)

To a solution of 5-fluoro-1H-benzoimidazole (0.50 g, 0.00367 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.44g, 0.011 mol). After addition, the resulting mixture was stirred for 2h.(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(1.29 g, 0.00367 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford 0.17 g of the desiredcompound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H, NH), 8.31 (d, J=17.2 Hz, 1H,ArH), 8.16-8.05 (m, 3H, ArH), 7.62-7.56 (m, 1H, ArH), 7.44 (dd, J=9.60Hz, J=2.4 Hz, 1H, ArH), 7.04 (dd, J=9.60 Hz, J=2.4 Hz, 1H, ArH), 6.49(s, 1H, OH), 4.65 (d, J=5.6 Hz, 1H, CH), 4.62 (d, J=5.6 Hz, 1H, CH),1.47 (s, 3H, CH₃). Mass (ESI, Negative): 404.8[M−H]⁻; (ESI, Positive):429.0[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-((S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)-3-(5-fluoro-1H-benzo[d]imidazol-1-yl)-2-methylpropanamide(C₃₁H₂₃F₇N₆O₄) (72)

This byproduct was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford 50 mg of the titledcompound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H, NH), 9.64 (s, 1H, NH), 8.31(d, J=17.2 Hz, 1H, ArH), 8.33-8.30 (m, 1H, ArH), 8.11-7.86 (m, 6H, ArH),7.54-7.52 (m, 1H, ArH), 7.35-7.33 (m, 1H, ArH), 6.77-6.73 (m, 1H, ArH),6.31 (s, 1H, OH), 4.66-4.63 (m, 1H, CH), 4.50-4.44 (m, 1H, CH),3.83-3.82 (m, 1H, CH), 3.66-3.64 (m, 1H, CH), 1.54 (s, 3H, CH₃), 1.34(s, 3H, CH₃). Mass (ESI, Negative): 675.0[M−H]⁻; (ESI, Positive):699.3[M+Na]⁺.

To a solution of 5,6-difluoro-1H-benzoimidazole (0.23 g, 0.00148 mol) inanhydrous THF (10 mL), which was cooled in an dry-ice acetone bath underan argon atmosphere, was added LDA (2.0 M in THF, 1.11 mL, 0.0022 mol).After addition, the resulting mixture was stirred for 2 h.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.40 g, 0.00148 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford the desired compound aswhite solid.

(S)—N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(5,6-difluoro-benzoimidazol-1-yl)-2-hydroxy-2-methyl-propionamide(C₁₉H₁₃F₅N₄O₂) (73)

¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H, NH), 8.25 (d, J=2.0 Hz, 1H,ArH), 8.21 (s, 1H, ArH), 8.14 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.06(d, J=8.8 Hz, 1H, ArH), 7.43-7.40 (m, 1H, ArH), 7.26-7.19 (m, 1H, ArH),6.51 (s, 1H, OH), 4.65 (d, J=14.8 Hz, 1H, CH), 4.41 (d, J=14.8 Hz, 1H,CH), 1.42 (s, 3H, CH₃). Mass (ESI, Negative): 422.7 [M−H]⁻; (ESI,Positive): 447.0 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-hydroxy-2-methylpropanamide(C₁₉H₁₃F₅N₄O₂) (74)

¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H, NH), 8.36 (d, J=2.0 Hz, 1H,ArH), 8.17 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 8.07(d, J=8.4 Hz, 1H, ArH), 7.44-7.41 (m, 1H, ArH), 7.21-7.14 (m, 1H, ArH),6.54 (s, 1H, OH), 4.62 (d, J=14.4 Hz, 1H, CH), 4.52 (d, J=14.4 Hz, 1H,CH), 1.41 (s, 3H, CH₃). Mass (ESI, Negative): 422.7[M−H]⁻; (ESI,Positive): 447.0[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-1H-benzo[d]imidazol-1-yl)-2-hydroxy-2-methylpropanamide(C₁₉H₁₄F₄N₄O₂) (75)

To a solution of 7-fluoro-benzimidazole (0.30 g, 0.0022 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.132g, 0.00331 mol). After addition, the resulting mixture was stirred fortwo hours.(R)-3-Bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide(0.77 g, 0.0022 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using methylenechloride and methanol (19:1) as eluent to afford 0.18 g of the titledcompound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H, NH), 8.39 (d, J=2.0 Hz, 1H,ArH), 8.21 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.11 (s, 1H, ArH), 8.08(d, J=8.8 Hz, 1H, ArH), 7.46 (d, J=8.0 Hz, 1H, ArH), 7.16-7.10 (m, 1H,ArH), 7.05-7.00 (m, 1H, ArH), 6.52 (s, 1H, OH), 4.64-4.56 (m, 2H, CH),1.35 (s, 3H, CH₃). Mass (ESI, Negative): 404.8[M−H]⁻.

Synthesis of Indazole SARDs:

To a solution of substituted-1H-indazole (0.00148 mol; e.g.,5-fluoro-1H-indazole for 90) in anhydrous THF (10 mL), which was cooledin an dry-ice acetone bath under an argon atmosphere, was added LDA (2.0M in THF, 1.11 mL, 0.0022 mol). After addition, the resulting mixturewas stirred for 2 h.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.40 g, 0.00148 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silicon gel column using methylenechloride and methanol (19:1) as eluent to afford the desired compound aswhite solid.

Example 3 Synthesis of Quinoline, Isoquinoline, and Indoline SARDCompounds of this Invention

Quinoline Compounds

Isoquinoline Compounds

Indoline Compounds

General Procedure: Method A:

General scheme for the synthesis of indoline, quinoline and isoquinolinederivatives

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2R)

D-Proline (1R) (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOHand cooled in an ice bath; the resulting alkaline solution was dilutedwith acetone (71 mL). An acetone solution (71 mL) of methacryloylchloride (13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) weresimultaneously added over 40 min to the aqueous solution of D-proline inan ice bath. The temperature of the mixture was kept at 10-11° C. duringthe addition of the methacryloyl chloride. After stirring (3 h, roomtemperature (RT)), the mixture was evaporated in vacuo at a temperatureat 35-45° C. to remove acetone. The resulting solution was washed withethyl ether and was acidified to pH 2 with concentrated HCl. The acidicmixture was saturated with NaCl and was extracted with EtOAc (100 mL×3).The combined extracts were dried over Na₂SO₄, filtered through Celite®,and evaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (Marhefka, C. A.; Moore, B. M., 2nd; Bishop, T. C.; Kirkovsky, L.;Mukherjee, A.; Dalton, J. T.; Miller, D. D. Homology modeling usingmultiple molecular dynamics simulations and docking studies of the humanandrogen receptor ligand binding domain bound to testosterone andnonsteroidal ligands. J Med Chem 2001, 44, 1729-40) mp 102.5-103.5° C.;the NMR spectrum of this compound demonstrated the existence of tworotamers of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer,5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for bothrotamers, vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) forthe second rotamer (totally 1H for both rotamers, CH at the chiralcenter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H,CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3,169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437(OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178cm⁻¹; [α]_(D) ²⁶ +80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C,59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3R)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the(2R)-1-methacryloylpyrrolidin-2-carboxylic acid (2R) (16.1 g, 88 mmol)in 70 mL of DMF under argon at RT, and the resulting mixture was stirred3 days. The solvent was removed in vacuo, and a yellow solid wasprecipitated. The solid was suspended in water, stirred overnight at RT,filtered, and dried to give 18.6 g (81%) (smaller weight when dried 34%)of the titled bromolactone (3R) as a yellow solid: mp 158.1-160.3° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4 Hz,1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72(m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474,1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹;[α]_(D) ²⁶ +124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C,41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N, 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4R)

A mixture of bromolactone (3R) (18.5 g, 71 mmol) in 300 mL of 24% HBrwas heated at reflux for 1 h. The resulting solution was diluted withbrine (200 mL), and was extracted with ethyl acetate (100 mL×4). Thecombined extracts were washed with saturated NaHCO₃ (100 mL×4). Theaqueous solution was acidified with concentrated HCl to pH=1, which, inturn, was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d,J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me);

IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O), 1449, 1421, 1380,1292, 1193, 1085 cm⁻¹;

[α]_(D) ²⁶ +10.5° (c=2.6, MeOH);

Anal. Calcd. for C₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8S, X═CF₃)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (4R) (51.13 g, 0.28 mol) in 300 mL of THF under an argonatmosphere. The resulting mixture was stirred for 3 h under the samecondition. To this was added Et₃N (39.14 g, 0.39 mol) and stirred for 20min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at RT. Thesolvent was removed under reduced pressure to give a solid which wastreated with 300 mL of H₂O, extracted with EtOAc (2×400 mL). Thecombined organic extracts were washed with saturated NaHCO₃ solution(2×300 mL) and brine (300 mL). The organic layer was dried over MgSO₄and concentrated under reduced pressure to give a solid which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8S, X═CF₃) as a light-yellow solid. M.p. 134.0-136.5° C.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M−H]-349.0.

General Procedure for Preparation of Indoline, Quinoline andIsoquinoline Derivatives (Last Step):

Preparation of LDA Solution in THF.

To a stirred solution of freshly distilled diisopropylamine (0.14 mL,1.2 mmol) in anhydrous 5 mL of THF was added a solution ofn-butyllithium (0.53 mL, 1.32 mmol, 2.5 M solution in hexane) at −78° C.under argon atmosphere. The prepared solution of LDA or 2.0 M LDA wasslowly warmed to 0° C. and stirred for 10 min and cooled again to −78°C.

To the LDA solution was added dropwise a solution of 9S (1.0 mmol) in 5mL of THF for 20 min. The reaction mixture was stirred at the sametemperature for 30 min and quenched by addition of sat. NH₄Cl. Thesolution was concentrated under reduced pressure and dispersed intoexcess EtOAc and dried over Na₂SO₄. The solution was concentrated andthe resulting solid was recrystallized from EtOAc/hexane or DCM/hexaneto give desired compound 10S. The mother liquor was concentrated andpurified by flash column chromatography (EtOAc/hexane) to giveadditional 10S.

Alternative Procedure for Preparation of Indoline Compounds (Last Step):

NaH of 60% dispersion in mineral oil (61 mg, 1.5 mmol) was added in 5 mLof anhydrous THF solvent into a 50 mL dried two necked round bottomflask equipped with a dropping funnel. 5-Fluoroindoline or5-bromoindoline (1.48 mmol) was added to the solution under argonatmosphere in an ice-water bath, and the resulting solution was stirredfor 30 min in an ice-water bath. Into the flask, the prepared solutionof the oxirane:(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide,(1.48 mmol in THF) was added through dropping funnel under argonatmosphere in an ice-water bath and stirred overnight at RT. Afteradding 1 mL of H₂O, the reaction mixture was condensed under reducedpressure, and then dispersed into 20 mL of EtOAc, washed with 20 mL (×2)water, brine, dried over anhydrous Na₂SO₄, and evaporated to dryness.The mixture was purified with flash chromatography (EtOAc/hexane 40%solvent, SIO₂) and afforded the desired products 100 or 102.

(S)-3-(5-Bromoindolin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(100)

Yield 45%; Light brown solid; MS (ESI) 466.3 [M−H]⁻; ¹H NMR (CDCl₃, 400MHz) δ 9.17 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.49 (d, J=8.4 Hz,1H), 3.66 (d, J=14.4 Hz, 1H), 3.48 (bs, 1H, OH), 3.47-3.41 (m, 1H), 3.34(q, J=9.2 Hz, 1H), 3.25 (d, J=14.4 Hz, 1H), 3.00-2.91 (m, 2H), 1.56 (s,3H).

(S)-3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (134)

Yield; 62%; MS (ESI) m/z 481.6 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.19(bs, 1H, NH), 8.00 (s, 1H), 7.97-7.92 (m, 1H), 7.78 (d, J=8.4 Hz, 1H),7.12 (dd, J=8.8, 2.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.8 Hz,1H), 3.86 (d, J=15.2 Hz, 1H), 3.45 (d, J=15.2 Hz, 1H), 3.21 (t, J=5.4Hz, 2H), 2.74 (m, 2H), 1.87 (m, 2H), 1.60 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(101)

Yield; 68%; MS (ESI) m/z 406.0 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.21(bs, 1H, NH), 8.10 (d, J=2.4 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.89(d, J=8.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.47 (t, J=8.4 Hz, 1H), 6.39 (d,J=8.0 Hz, 1H), 3.69 (d, J=14.4 Hz, 1H), 3.53 (bs, 1H, OH), 3.50 (m, 1H),3.40 (q, J=8.0 Hz, 1H), 3.29 (d, J=14.4 Hz, 1H), 3.09 (m, 1H), 2.99 (m,1H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(102)

Yield; 75%; MS (ESI) m/z 406.0 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.24(bs, 1H, NH), 8.10 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.8, 2.2 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 6.83 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (m. 1H), 6.52 (dd,J=8.4, 4.0 Hz, 1H), 3.75 (bs, 1H, OH), 3.64 (d, J=14.0 Hz, 1H), 3.44 (m,1H), 3.30 (q, J=9.2 Hz, 1H), 3.22 (d, J=14.0 Hz, 1H), 2.94 (m, 2H), 1.56(s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-hydroxy-2-methylpropanamide(135)

Yield; 42%; MS (ESI) m/z 420.0 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.25(bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.4, 2.0 Hz, 1H), 7.80(d, J=8.4 Hz, 1H), 6.78-6.69 (m, 1H), 6.77 (m. 3H), 3.88 (d, J=15.2 Hz,1H), 3.82 (bs, 1H, OH), 3.36 (d, J=15.2 Hz, 1H), 3.16 (m, 2H), 3.16-2.70(m, 2H), 1.94-1.83 (m, 2H), 1.56 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropanamide(131)

Yield; 43%; MS (ESI) m/z 419.9 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.51(bs, 1H, NH), 8.10 (d, J=1.8 Hz, 1H), 7.95 (dd, J=8.6, 1.8 Hz, 1H), 7.79(d, J=8.6 Hz, 1H), 6.88 (m, 1H), 6.81 (m. 2H), 3.69 (s, 2H), 3.42 (d,J=13.2 Hz, 1H), 2.91 (m, 4H), 2.60 (d, J=13.2 Hz, 1H), 2.17 (s, 1H, OH),1.46 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(6-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(105)

Yield; 70%; MS (ESI) m/z 405.9 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.21(bs, 1H, NH), 8.10 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz,1H), 6.98 (t, J=6.8 Hz, 1H), 6.41 (t, J=7.6 Hz, 1H), 3.35 (m, 1H), 3.66(d, J=14.0 Hz, 1H), 3.52 (bs, 1H, OH), 3.47 (m, 1H), 3.41 (q, J=9.2 Hz,1H), 3.24 (d, J=14.0 Hz, 1H), 3.00-2.87 (m, 2H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropanamide(132)

Yield; 69%; MS (ESI) 420.0 [M−H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs,1H, NH), 7.93 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.0Hz, 1H), 6.86 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 3.71 (s, 2H), 3.42 (d,J=13.2 Hz, 1H), 2.91-2.82 (m, 5H), 2.60 (d, J=13.2 Hz, 1H), 1.46 (s,3H).

Example 4 Synthesis of SARD Compounds of this Invention

Method A.

General Scheme for Preparation of Indoline, Quinolone and IsoquinolineDerivatives

Preparation of LDA solution in THF: To a stirred solution of freshlydistilled diisopropylamine (0.14 mL, 1.2 mmol) in anhydrous 5 mL of THFwas added a solution of n-butyllithium (0.53 mL, 1.32 mmol, 2.5 Msolution in hexane) at −78° C. under argon atmosphere. The preparedsolution of LDA or commercial 2.0 M LDA was slowly warmed to 0° C. andstirred for 10 min and cooled again to −78° C. To the LDA solution wasadded dropwise a solution of 9 (1.0 mmol) in 5 mL of THF for 20 min. 8Rin THF was added dropwise through dropping funnel under argon atmosphereat −78° C. The reaction mixture was stirred at the same temperature for30 min and quenched by addition of sat. NH₄Cl. The solution wasconcentrated under reduced pressure and dispersed into excess EtOAc anddried over Na₂SO₄. The solution was concentrated and the resulting solidwas recrystallized from EtOAc/hexane or DCM/hexane to give designedcompound 10. The mother liquor was concentrated and purified by flashcolumn chromatography (EtOAc/hexane) to give the 10 additionally.

Method B.

Preparation of Indoles and Carbazoles

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 20mL of anhydrous THF solvent into a 100 mL dried two necked round bottomflask equipped with a dropping funnel. Indole (12, 2.84 mmol) was addedto the solution under argon atmosphere in ice-water bath, and theresulting solution was stirred for 30 min at the ice-water bath. Intothe flask, epoxide 11 (2.84 mmol in THF) was added through droppingfunnel under argon atmosphere at the ice-water bath and stirredovernight at room temperature. After adding 1 mL of H₂O, the reactionmixture was condensed under reduced pressure, and then dispersed into 50mL of EtOAc, washed with 50 mL (×2) water, brine, dried over anhydrousMgSO₄, and evaporated to dryness. The mixture was purified with flashcolumn chromatography with an eluent of EtOAc/hexane, and then thecondensed compounds were then recrystallized in EtOAc/hexane to give atarget product 13.

(S)—N-(3-Chloro-4-cyanophenyl)-2-methyloxirane-2-carboxamide (epoxideintermediate)

Yield 98%;

Light Brown solid;

MS (ESI) m/z 235.4 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) □ 400 MHz) H] idH), 7.90 (d, J=2.0 Hz, 1H), 7.61(d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 2.99 (s, 2H), 1.67 (s,3H).

Indole Derivatives

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(33)

To a solution of 5-fluoro-6-phenyl-1H-indole (0.37 g, 0.00175 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.11g, 0.00263 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.47 g, 0.002175 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.83 g(98%) of the titled compound as off-white foam.

¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H, NH), 8.28 (s, 1H, ArH), 8.08(d, J=8.8 Hz, 1H, ArH), 7.96 (d, J=8.8 Hz, 1H, ArH), 7.58 (d, J=6.8 Hz,1H, ArH), 7.49-7.31 (m, 7H, ArH), 6.42 (d, J=3.2 Hz, 1H, ArH), 6.35 (s,1H, OH), 4.61 (d, J=14.4 Hz, 1H, CH), 4.35 (d, J=14.4 Hz, 1H, CH), 1.46(s, 3H, CH₃).

Mass (ESI, Negative): 479.9[M−H]⁻; (ESI, Positive): 504.1[M+Na]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(34) 5-Fluoro-6-phenyl-1H-indole (C₁₄H₁₀FN)

To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄,0.54 g, 0.467 mmol] in 20 mL of ethylene glycol dimethyl ether (DME) wasadded 6-bromo-5-fluoroindole (1.00 g, 4.67 mmol), and the mixture wasstirred for 15 minutes under argon at room temperature. A solution ofphenylboronic acid (0.57 g, 4.67 mmol) in 2-3 mL of ethanol was addedand the mixture was stirred for 10 minutes under the same conditions. Asolution of potassium carbonate (0.97 g, 7.01 mmol) in 2 mL of water wasadded to above mixture and the resulting reaction mixture was heated atreflux for 3-4 hours under the argon atmosphere. After the end of thereaction was established by TLC, the reaction was diluted by brine,extracted with ethyl acetate. The organic layer was washed with brine,dried with MgSO₄, filtered, and concentrated under vacuum. The productwas purified by a silica gel column using ethyl acetate and hexanes(1:3) as eluent to afford 0.90 g (92% yield) of the titled compound aslight brown solid.+

To a solution of 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.000947 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.076g, 0.00189 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.30 g, 0.000947 mol) was added to the above solution, and theresulting reaction mixture was allowed to stir overnight at roomtemperature under argon. The reaction was quenched by water, extractedwith ethyl acetate. The organic layer was washed with brine, dried withMgSO₄, filtered, and concentrated under vacuum. The product was purifiedby a silica gel column using ethyl acetate and hexanes (1:2) as eluentto afford 0.26 g of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H, NH), 8.04 (d, J=1.6 Hz, 1H,ArH), 7.80 (d, J=8.8 Hz, 1H, ArH), 7.74 (dd, J=8.2 Hz, J=2.0 Hz, 1H,ArH), 7.62 (d, J=6.4 Hz, 1H, ArH), 7.51-7.44 (m, 4H, ArH), 7.39-7.32 (m,3H, ArH), 6.42 (d, J=3.2 Hz, 1H, ArH), 6.33 (s, 1H, OH), 4.60 (d, J=15.2Hz, 1H, CH), 4.35 (d, J=15.2 Hz, 1H, CH), 1.45 (s, 3H, CH₃).

Mass (ESI, Negative): 445.8[M−H]⁻; (ESI, Positive): 470.0[M+Na]⁺.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(6-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(35)

Method B

Yield 67%;

White solid;

MS (ESI) m/z 376.9 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.67 (bs, 1H, NH), 7.79 (d, J=2.0 Hz, 1H),7.56 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 5.4 Hz, 1H), 7.38 (dd, J=8.4,2.0 Hz, 1H), 7.13 (dd, J=10.0, 2.0 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.86(m, 2H), 6.48 (d, J=3.2 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 4.28 (d,J=14.8 Hz, 1H), 2.61 (bs, 1H, OH), 1.60 (s, 3H);

¹⁹F NMR (CDCl₃) δ −120.03.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(36)

Method B

Under argon atmosphere into a 100 mL, dried, two-necked round bottomflask equipped with a dropping funnel in ice-water bath, NaH of 60%dispersion in mineral oil (228 mg, 5.70 mmol) was added in 20 mL ofanhydrous THF solvent into the flask and 4-fluoroindole (390 mg, 2.84mmol) solution in 10 mL of anhydrous THF was added to the solution underthe argon atmosphere in the ice-water bath, and then the resultingsolution was stirred at the ice-water bath. After 30 min, into theflask, a solution of(S)—N-(3-chloro-4-cyanophenyl)-2-methyloxirane-2-carboxamide (2.84 mmolin THF) was added through dropping funnel under argon atmosphere at theice-water bath and stirred overnight at room temperature. After adding 1mL of H₂O, the reaction mixture was condensed under reduced pressure,and then dispersed into 50 mL of EtOAc, washed with 50 mL (×2) water,brine, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentEtOAc/hexane, and then the condensed compounds were then recrystallizedin EtOAc/hexane to give a target product, 36.

Yield 73%;

White solid;

MS (ESI) m/z 369.9 [M−H]⁻; HRMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915. Found: 372.0915 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.64 (bs, 1H, NH), 7.81 (s, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.14-7.10(m, 2H), 6.77 (t, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.60 (s, 1H),4.64 (d, J=14.8 Hz, 1H), 4.35 (d, J=14.8 Hz, 1H), 2.48 (bs, 1H, OH),1.60 (s, 3H);

¹³C NMR (acetone-d₆, 100 MHz) δ 174.8, 158.1, 155.7, 144.3, 141.5 (d,J=11.0 Hz), 137.2, 135.5, 130.7, 122.4 (d, J=7.0 Hz), 121.0, 119.3,118.0 (d, J=22.0 Hz), 116.6, 107.9 (t, J=5.0 Hz), 104.4 (d, J=19.0 Hz),97.7, 77.6, 55.0, 24.2.

¹⁹F NMR (CDCl₃, decoupled) δ −121.78.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(37)

Method B

Yield 79%;

White solid;

MS (ESI) m/z 371.0 [M−H]⁻; HRMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915. Found: 372.0922 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.62 (bs, 1H, NH), 7.80 (d, J=2.0 Hz, 1H),7.56 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 2H), 7.23 (dd, J=9.2, 2.4 Hz, 1H),7.15 (d, J=3.2 Hz, 1H), 7.22 (dt, J=9.2, 2.8 Hz, 1H), 6.47 (d, J=3.2 Hz,1H), 4.63 (d, J=14.8 Hz, 1H), 4.32 (d, J=14.8 Hz, 1H), 2.49 (bs, 1H,OH), 1.60 (s, 3H);

¹⁹F NMR (CDCl₃) δ −124.52.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(3-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(38)

Method B

Yield 68%;

Mp 168.9-170.1° C.;

Light Brown solid;

MS (ESI) m/z 369.8 [M−H]⁻; LCMS (ESI) m/z calcd for C₁₉H₁₆ClFN₃O₂:372.0915. Found: 372.0910 [M+H]⁺.

¹H NMR (CDCl₃, 400 MHz) δ 8.66 (bs, 1H, NH), 7.81 (d, J=2.0 Hz, 1H),7.60-7.56 (m, 2H), 7.37 (dd, J=8.4, 2.0 Hz, 2H), 7.23 (m, 1H), 7.12 (t,J=7.4 Hz, 1H), 6.93 (d, J=2.8 Hz, 1H), 4.56 (d, J=15.2 Hz, 1H), 4.27 (d,J=15.2 Hz, 1H), 2.44 (s, 1H, OH), 1.59 (s, 3H).

¹⁹F NMR (CDCl₃) δ −173.91

(S)—N-(3-Chloro-4-cyanophenyl)-3-(7-fluoro-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(39)

Method B

Yield 73%;

White solid;

MS (ESI) m/z 370.0 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.60 (bs, 1H, NH), 8.82 (d, J=2.0 Hz, 1H),7.55 (d, J=8.4 Hz, 1H), 7.37-7.34 (m, 2H), 7.02 (d, J=3.2 Hz, 1H), 7.00(m, 1H), 7.01-6.98 (m, 1H), 6.91 (m, 1H), 6.46 (t, J=2.8 Hz, 1H), 4.68(d, J=15.0 Hz, 1H), 4.62 (d, J=15.0 Hz, 1H), 2.73 (d, J=4.4 Hz, 1H, OH),1.61 (s, 3H);

¹⁹F NMR (CDCl₃) δ −133.54.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-3-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(40)

To a solution of 5-fluoro-3-phenyl-1H-indole (0.50 g, 0.002267 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.24g, 0.005918 mol). After addition, the resulting mixture was stirred forthree hours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.75 g, 0.002267 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2 to 1:1) as eluent to afford0.43 g of the titled compound as yellowish solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H, NH), 8.06 (d, J=2.0 Hz, 1H,ArH), 7.86-7.79 (m, 2H, ArH), 7.64 (s, 1H, ArH), 7.62-7.58 (m, 1H, ArH),7.55-7.52 (m, 2H, ArH), 7.50 (dd, J=10.4 Hz, J=2.4 Hz, 1H, ArH),7.43-7.40 (m, 2H, ArH), 7.26-7.22 (m, 1H, ArH), 7.03-6.98 (m, 1H, ArH),6.37 (s, 1H, OH), 4.60 (d, J=14.8 Hz, 1H, CH), 4.38 (d, J=14.8 Hz, 1H,CH), 1.46 (s, 3H, CH₃).

Mass (ESI, Negative): 446.8[M−H]⁻; (ESI, Positive): 448.1248[M+H]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(4-phenyl-1H-indol-1-yl)propanamide(41) Phenyl-1H-indole (C₁₄H₁₁N)

To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄,1.179 g, 1.0212 mmol] in 40 mL of ethylene glycol dimethyl ether (DME)was added 4-bromo-indole (2.00 g, 10.202 mmol), and the mixture wasstirred for 15 minutes under argon at room temperature. A solution ofphenylboronic acid (1.24 g, 10.202 mmol) in 4.5 mL of ethanol was addedand the mixture was stirred for 10 minutes under the same conditions. Asolution of potassium carbonate (2.16 g, 15.306 mmol) in 3.5 mL of waterwas added to above mixture and the resulting reaction mixture was heatedat reflux for 3-4 hours under the argon atmosphere. After the end of thereaction was established by TLC, the reaction was diluted by brine,extracted with ethyl acetate. The organic layer was washed with brine,dried with MgSO₄, filtered, and concentrated under vacuum. The productwas purified by a silica gel column using ethyl acetate and hexanes (1:3to 2:1) as eluent to afford 1.67 g (84.8% yield) of the titled compoundas yellowish oil.

To a solution of 4-phenyl-1H-indole (0.42 g, 0.002173 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.22 g,0.005434 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.76 g, 0.002173 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.69 g(69%) of the titled compound as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H, NH), 8.37 (d, J=2.0 Hz, 1H,ArH), 8.18 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.4 Hz, 1H,ArH), 7.60-7.54 (m, 3H, ArH), 7.49-7.45 (m, 2H, ArH), 7.38-7.34 (m, 2H,ArH), 7.18-7.14 (m, 1H, ArH), 7.04 (d, J=7.2 Hz, 1H, ArH), 6.51 (d,J=3.2 Hz, 1H, ArH), 6.35 (s, 1H, OH), 4.58 (d, J=14.4 Hz, 1H, CH), 4.38(d, J=14.4 Hz, 1H, CH), 1.45 (s, 3H, CH₃).

Mass (ESI, Positive): 464.1536[M+H]⁺; 486.1351 [M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-5-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(42)

To a solution of 4-fluoro-5-phenyl-1H-indole (0.33 g, 0.00156 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.16g, 0.00391 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.55 g, 0.00156 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.47 g(63%) of the titled compound as off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.35 (d, J=2.0 Hz, 1H,ArH), 8.17 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.4 Hz, 1H,ArH), 7.51-7.40 (m, 5H, ArH), 7.36-7.32 (m, 2H, ArH and indole-H),7.17-7.13 (m, 1H, ArH), 6.53 (d, J=3.2 Hz, 1H, ArH), 6.38 (s, 1H, OH),4.60 (d, J=14.8 Hz, 1H, CH), 4.38 (d, J=14.8 Hz, 1H, CH), 1.45 (s, 3H,CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): 482.1490[M+H]⁺;504.1310[M+Na]⁺.

Carbazole

Methods A and B: Preparation of Carbazoles

Method A (Non Microwave):

A mixture of phenyl trifluoromethanesulfonate (500 mg, 2.21 mmol),palladium acetate (II) (50 mg, 0.22 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (317 mg, 0.66 mmol) andcesium carbonate (1.09 g, 3.31 mmol) in 50 mL of toluene were inertizedwith argon. Then, substituted aniline (2.43 mmol) was added and themixture was heated at 110° C. overnight. The reaction mixture wasallowed to cool to room temperature and filtered through a pad ofCelite®. The filtrate was diluted with CH₂Cl₂ and water. The phases wereseparated and the aqueous phase was reextracted 2 times with CH₂Cl₂. Thecombined organic phases were dried over Na₂SO₄ and the solvent wasevaporated.

Method B (Microwave):

A mixture of phenyl trifluoromethanesulfonate (200 mg, 0.88 mmol),palladium acetate (II) (20 mg, 0.09 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (64 mg, 0.13 mmol) andcesium carbonate (430 mg, 1.32 mmol), and substituted aniline (0.97mmol) in 5 mL of toluene were loaded into a vessel with a cap. Reactionvessels were placed in a reactor block in the microwave. A programmablemicrowave irradiation cycle of 30 min at 300 W at 110° C. and 25 min offan-cooling was executed (irradiation time, 30 min). The mixture wastransferred to a round bottom flask to be concentrated under reducedpressure and poured into EtOAc, which was washed with water and driedover anhydrous MgSO₄, concentrated. The crude product obtained waspurified by chromatography on silica gel using EtOAc/hexane (6/1, v/v)as an eluent to produce the target product (˜89%) as deep brown oil.

4-Fluoro-N-phenyl aniline

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.24 (m, 2H), 7.07-7.02 (m, 2H),7.01-6.95 (m, 4H), 6.89 (t, J=7.2 Hz, 1H), 5.57 (bs, 1H, NH).

3-Nitro-9H-carbazole

A mixture of phenyl trifluoromethanesulfonate (500 mg, 2.21 mmol),palladium acetate (II) (50 mg, 0.22 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (317 mg, 0.66 mmol) andcesium carbonate (1.09 g, 3.31 mmol) in 50 mL of toluene were inertizedwith argon. Then, 4-nitroaniline (331 mg, 2.43 mmol) was added and themixture was heated at 110° C. overnight. The reaction mixture wasallowed to cool to room temperature and filtered through a pad ofCelite®. The filtrate was diluted with CH₂Cl₂ and water. The phases wereseparated and the aqueous phase was re-extracted 2 times with CH₂Cl₂.The combined organic phases were dried over Na₂SO₄ and the resultingsolution was dried over anhydrous Na₂SO₄ and purified with flash columnchromatography as an eluent EtOAc/hexane (1/6, v/v) to give4-nitro-N-phenylaniline. The aniline (450 mg, 2 mmol), Pd(OAc)₂ (23 mg,0.1 mmol), K₂CO₃ (30 mg, 0.2 mmol), and pivalic acid (408 mg, 4 mmol)was placed into a glass test tube. The uncapped test tube was placed inan oil bath and the mixture was stirred under air at the indicatedtemperature. The solution was then cooled to room temperature, dilutedwith EtOAc, washed with a saturated Na₂CO₃, dried over Na₂SO₄,concentrated, and purified by flash column chromatography as an eluentof EtOAc/hexane to give 3-nitro-9H-carbazole.

(S)-3-(9H-Carbazol-9-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(200)

Method B:

Yield 88%; MS (ESI) m/z 436.1 [M−H]⁻;

¹H NMR (CDCl₃, 400 MHz) δ 8.82 (bs, 1H, NH), 8.09-8.06 (m, 3H), 7.84 (d,J=1.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.45-7.39 (m,3H), 7.24-7.23 (m, 2H), 4.80 (d, J=15.2 Hz, 1H), 4.63 (d, J=15.2 Hz, 1H)2.57 (s, 1H, OH), 1.69 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-nitro-9H-carbazol-9-yl)propanamide(201)

Method B:

MS (ESI) m/z 481.1 [M−H]⁻

¹H NMR (CDCl₃, 400 MHz) δ 9.01 (s, 1H), 8.92 (bs, 1H, NH), 8.39 (m, 1H),8.08 (m, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.62 (dd,J=8.4, 1.6 Hz, 1H), 7.45 (m, 1H), 7.48-7.22 (m, 3H), 4.91 (d, J=15.0 Hz,1H), 4.85 (d, J=15.0 Hz, 1H) 2.62 (s, 1H, OH), 1.70 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(202)

To a solution of 4-fluoro-carbazole (0.20 g, 0.00108 mol) in anhydrousTHF (10 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.09 g,0.00216 mol). After addition, the resulting mixture was stirred for twohours.(R)-3-Bromo-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide(0.38 g, 0.00108 mol) was added to the above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using methylenechloride as eluent to afford 0.36 g (73.5%) of the titled compound aswhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H, NH), 8.25 (d, J=1.6 Hz, 1H,ArH), 8.12-8.09 (m, 2H, ArH), 8.04 (d, J=8.8 Hz, 1H, ArH), 7.95 (dd,J=9.2 Hz, J=2.1 Hz, 1H, ArH), 7.66 (t, J=4.8 Hz, 1H, ArH), 7.64 (s, 1H,ArH), 7.37 (dt, J=9.2 Hz, J=1.2 Hz, 1H, ArH), 7.20 (td, J=9.2 Hz, J=2.0Hz, 1H, ArH), 7.13 (t, J=8.0 Hz, 1H, ArH), 6.34 (s, 1H, OH), 4.70 (d,J=14.8 Hz, 1H, CH), 4.55 (d, J=14.8 Hz, 1H, CH), 1.52 (s, 3H, CH3).

Mass (ESI, Negative): 453.9 [M−H]−; (ESI, Positive): 478.1 [M+Na]+.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(3-fluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(203)

To a solution of 3-fluoro-carbazole (0.10 g, 0.00054 mol) in anhydrousTHF (5 mL), which was cooled in an ice water bath under an argonatmosphere, was added sodium hydride (60% dispersion in oil, 0.033 g,0.00081 mol). After addition, the resulting mixture was stirred for twohours.(R)-3-Bromo-N-(4-cyano-3-chloro-phenyl)-2-hydroxy-2-methylpropanamide(0.17 g, 0.00054 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was dried with MgSO₄, filtered, and concentrated undervacuum. The product was purified by a silica gel column using hexanesand ethyl acetate (2:1) as eluent to afford 0.22 g (98%) of the titledcompound as white solid/needles.

¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H, NH), 8.12 (d, J=7.6 Hz, 1H,ArH), 8.05 (d, J=2.0 Hz, 1H, ArH), 7.96 (dd, J=9.2 Hz, J=2.0 Hz, 1H,ArH), 7.86 (d, J=8.8 Hz, 1H, ArH), 7.80 (dd, J=8.4 Hz, J=2.0 Hz, 1H,ArH), 7.69-7.66 (m, 2H, ArH), 7.41 (t, J=8.0 Hz, 1H, ArH), 7.24 (dt,J=9.6 Hz, J=2.4 Hz, 1H, ArH), 7.16 (t, J=7.2 Hz, 1H, ArH), 6.34 (s, 1H,OH), 4.70 (d, J=15.2 Hz, 1H, CH), 4.54 (d, J=15.2 Hz, 1H, CH), 1.52 (s,3H, CH₃).

Mass (ESI, Negative): 420.1[M−H]⁻; (ESI, Positive): 444.1[M+Na]⁺.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3,6-difluoro-9H-carbazol-9-yl)-2-hydroxy-2-methylpropanamide(204)

To a solution of 3,6-difluorocarbazole (0.20 g, 0.00098 mol) inanhydrous THF (10 mL), which was cooled in an ice water bath under anargon atmosphere, was added sodium hydride (60% dispersion in oil, 0.06g, 0.001476 mol). After addition, the resulting mixture was stirred forthree hours.(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(0.266 g, 0.00098 mol) was added to above solution, and the resultingreaction mixture was allowed to stir overnight at room temperature underargon. The reaction was quenched by water, extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.40 gof the titled compound as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H, NH), 8.22 (d, J=1.6 Hz, 1H,ArH), 8.11 (dd, J=8.8 Hz, J=2.0 Hz, 1H, ArH), 8.05 (d, J=8.8 Hz, 1H,ArH), 7.98 (d, J=2.4 Hz, 1H, ArH), 7.96 (d, J=2.4 Hz, 1H, ArH),7.68-7.65 (m, 2H, ArH), 7.27-7.22 (m, 2H, ArH), 6.36 (s, 1H, OH), 4.72(d, J=15.2 Hz, 1H, CH), 4.54 (d, J=15.2 Hz, 1H, CH), 1.53 (s, 3H, CH₃).

Mass (ESI, Negative): 471.9[M−H]⁻; (ESI, Positive): 496.1[M+Na]⁺.

(S)-3-(9H-Carbazol-9-yl)-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(205)

Method B

Yield 77%;

MS (ESI) m/z 402.3 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 8.75 (bs, 1H, NH), 8.08 (d, J=7.6 Hz, 2H),7.78 (d, J=1.6 Hz, 1H), 7.56-7.54 (m, 3H), 7.44 (t, J=7.6 Hz, 2H), 7.37(dd, J=8.8, 1.8 Hz, 1H), 7.27-7.25 (m, 2H), 4.78 (d, J=15.6 Hz, 1H),4.63 (d, J=15.6 Hz, 1H), 2.65 (bs, 1H, OH), 1.66 (s, 3H).

Isoquinoline

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy-2-methylpropanamide(132)

Method A

Yield 69%;

MS (ESI) m/z 420.0 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs, 1H, NH), 7.93 (d, J=8.4 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.86 (m, 1H), 6.63 (d,J=8.0 Hz, 1H), 3.71 (s, 2H), 3.42 (d, J=13.2 Hz, 1H), 2.91-2.82 (m, 5H),2.60 (d, J=13.2 Hz, 1H), 1.46 (s, 3H).

Indoline Derivatives

(S)—N-(3-Chloro-4-cyanophenyl)-3-(4-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(103)

Preparation of LDA solution in THF.To a stirred solution of freshly distilled diisopropylamine (0.14 mL,1.2 mmol) in anhydrous 5 mL of THF was added a solution ofn-butyllithium (0.53 mL, 1.32 mmol, 2.5 M solution in hexane) at −78° C.under argon atmosphere.Under the argon atmosphere into a 100 mL dried two necked round bottomflask equipped with a dropping funnel, the prepared solution of LDA orcommercial 2.0 M LDA solution (1.2 mmol, Aldrich) in THF was placed inthe flask, and then 4-fluoroindoline (1.0 mmol) in 10 mL of anhydrousTHF was dropwise added to the LDA solution at the −78° C. under argonatmosphere. The solution was stirred for 10 min and warmed to 0° C. andcooled down again to −78° C. To the solution, a solution of(R)-3-bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(1.0 mmol in THF) was added through dropping funnel under argonatmosphere at −78° C. and allowed to warm gradually to room temperatureand stirred overnight. And then quenched by an addition of 0.5 mL ofsat. NH₄Cl. The solution was reduced in volume under reduced pressureand dispersed into excess EtOAc, and then dried over anhydrous MgSO₄.The solution was concentrated on and purified by flash columnchromatography (EtOAc/hexane) or recrystallized from EtOAc/hexane (orDCM/hexane) to give the designed compound, 573.

Yield 71%;

White solid;

MS (ESI) m/z 372.0 [M−H]⁻;

HRMS (ESI) m/z calcd for C₁₉H₁₈ClFN₃O₂: 374.1072. Found: 374.1072[M+H]⁺.

[α]_(D) ²⁰ −173° (c 1.0, CH₃OH);

¹H NMR (acetone-d₆, 400 MHz) δ 9.84 (bs, 1H, NH), 8.26 (d, J=2.0 Hz,1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.99 (m, 1H),6.43 (d, J=8.0 Hz, 1H), 6.31 (t, J=8.4 Hz, 1H), 5.21 (bs, 1H, OH), 3.66(m, 1H), 3.63 (d, J=14.4 Hz, 1H), 3.53 (q, J=8.0 Hz, 1H), 3.26 (d,J=14.4 Hz, 1H), 2.89 (m, 2H), 1.53 (s, 3H).

¹³C NMR (acetone-d₆, 100 MHz) δ 175.9, 160.6 (d, J=239.7 Hz), 160.6 (d,J=9.3 Hz), 144.6, 137.3, 135.6, 129.9 (d, J=8.7 Hz), 120.8, 119.2,116.7, 114.8 (d, J=21.7 Hz), 107.8, 105.1 (d, J=21.0 Hz), 104.1 (d,J=8.0 Hz), 77.8, 60.4, 56.7, 25.4, 24.3.

¹⁹F NMR (CDCl₃, decoupled) δ 118.95.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(104)

Method A

Yield; 68%;

¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs, 1H, NH), 7.98 (d, J=2.0 Hz, 1H),7.61 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (m, 1H), 6.77(m, 1H), 6.51 (m, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.56 (bs, 1H, OH), 3.42(m, 1H), 3.30 (q, J=9.2 Hz, 1H), 3.21 (d, J=14.4 Hz, 1H), 3.01 (t, J=8.4Hz, 2H), 1.54 (s, 3H).

MS (ESI) m/z 372.0 [M−H]⁻;

[α]_(D) ²⁰ −202° (c 1.0, CH₃OH)

¹⁹F NMR (CDCl₃, decoupled) δ 125.35.

(S)—N-(3-Chloro-4-cyanophenyl)-3-(6-fluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(106)

Method A

Yield 76%;

MS (ESI) m/z 372.1 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.08 (bs, 1H, NH), 7.97 (d, J=1.6 Hz, 1H),7.60 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 6.77 (t, J=6.4 Hz,1H), 6.39 (m, 1H), 6.33 (d, J=10.0 Hz, 1H), 3.64 (d, J=14.2 Hz, 1H),3.49 (bs, 1H, OH), 3.47 (m, 1H), 3.38 (q, J=9.2 Hz, 1H), 3.23 (d, J=14.2Hz, 1H), 2.95 (m, 2H), 1.56 (s, 3H).

(S)-3-(5-Chloro-6-fluoroindolin-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(107)

Method A

Yield; 47%

MS (ESI) m/z 440.3 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.15 (bs, 1H, NH), 8.08 (s, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.42 (d,J=10.0 Hz, 1H), 3.66 (d, J=14.4 Hz, 1H), 3.52-3.42 (m, 2H), 3.38 (s, 1H,OH), 3.21 (d, J=14.4 Hz, 1H), 2.96-2.80 (m, 2H), 1.52 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5,6-difluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(108)

Method A

Yield; 59%

MS (ESI) m/z 423.9 [M−H]⁻

¹H NMR (400 MHz, CDCl₃) δ 9.18 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H),7.97 (dd, J=8.4, 2.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.89 (t, J=8.8 Hz,1H), 6.43 (m, 1H), 3.64 (d, J=14.4 Hz, 1H), 3.46 (s, 1H, OH), 3.40-3.35(m, 2H), 3.17 (d, J=14.4 Hz, 1H), 2.99-2.91 (m, 2H), 1.57 (s, 3H).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(indolin-1-yl)-2-methylpropanamide(109)

Method A

Yield 69%;

MS (ESI) m/z 387.8 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.24 (bs, 1H, NH), 8.09 (d, J=2.0 Hz, 1H),7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.13-7.10 (m, 2H),6.78 (dt, J=8.0, 0.8 Hz, 1H), 6.62 (d, J=8.0, 1H), 3.77 (bs, 1H, OH),3.66 (d, J=14.4 Hz, 1H), 3.54 (t, J=8.4 Hz, 1H), 3.46-3.40 (m, 1H), 3.30(d, J=14.4 Hz, 1H), 3.04-2.92 (m, 2H), 1.57 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5,6-difluoroindolin-1-yl)-2-hydroxy-2-methylpropanamide(110)

Method A

Yield 64%;

MS (ESI) m/z 390.0 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.05 (bs, 1H, NH), 7.98 (s, 1H), 7.62 (d,J=8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 6.88 (t, J=8.8 Hz, 1H), 6.43 (m,1H), 3.64 (d, J=14.4 Hz, 1H), 3.46 (s, 1H, OH), 3.44 (m, 1H), 3.42-3.34(m, 1H), 3.16 (d, J=14.4 Hz, 1H), 3.95-3.88 (m, 2H), 1.55 (s, 3H).

(S)-3-(5-Bromoindolin-1-yl)-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropanamide(114)

Method A

Yield 54%;

MS (ESI) m/z 433.6 [M−H]⁻;

¹H NMR (400 MHz, CDCl₃) δ 9.04 (bs, 1H, NH), 7.98 (d, J=2.0 Hz, 1H),7.60 (d, J=6.0 Hz, 1H), 7.52 (dd, J=6.0, 2.0 Hz, 1H), 7.19-7.17 (m, 2H),6.49 (d, J=8.4 Hz, 1H), 3.65 (d, J=14.4, 1H), 3.47 (bs, 1H, OH),3.36-3.41 (m, 1H), 3.32 (q, J=9.2 Hz, 1H), 3.23 (d, J=14.4, 1H),2.99-2.91 (m, 2H), 1.56 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-6-phenylindolin-1-yl)-2-hydroxy-2-methylpropanamide(115)

To a solution of(S)—N-(3-chloro-4-cyanophenyl)-3-(5-fluoro-6-phenyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide(34, 0.185 g, 0.000413 mol) in 5 mL of glacial acetic acid, which wascooled in an ice-water bath, was added drop-wise sodium cyanoborohydride(1.0 M in THF, 0.62 mL, 0.00124 mol) under as argon atmosphere. Afteraddition, the resulting reaction mixture was allowed to stir forovernight at room temperature under argon. The reaction was quenched byaqueous NH₄Cl solution, extracted with ethyl acetate. The organic layerwas washed with brine twice, dried with MgSO₄, filtered, andconcentrated under vacuum. The product was purified by a silica gelcolumn using ethyl acetate and hexanes (1:2) as eluent to afford 0.17 gof the titled compound as yellowish foam.

¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H, NH), 8.21 (d, J=2.0 Hz, 1H,ArH), 7.92-7.84 (m, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 6.95 (d, J=10.4Hz, 1H, ArH), 6.55 (d, J=6.4 Hz, 1H, ArH), 6.02 (s, 1H, OH), 3.61 (q,J=8.8 Hz, 1H, CH), 4.50 (d, J=14.4 Hz, 1H, CH), 3.40 (d, J=14.4 Hz, 1H,CH), 4.19 (d, J=14.4 Hz, 1H, CH), 2.91 (t, J=8.4 Hz, 2H, CH₂), 1.42 (s,3H, CH₃).

Mass (ESI, Negative): [M−H]⁻; (ESI, Positive): 450.1394[M+H]⁺.

Indazole Derivatives

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(90, 91)

Method B

Yield; 67%

MS (ESI) 405.1 [M−H]⁻

¹H NMR (400 MHz, CDCl₃) δ 9.16 (bs, 1H, NH), 8.05-7.88 (m, 2H),7.81-7.72 (m, 2H), 7.62-7.13 (m, 4H), 6.72 (bs, OH, 0.56H), 6.15 (s, OH,0.44H), 4.94 (d, J=13.6 Hz, 0.56H), 4.95 (d, J=14.2 Hz, 0.46H), 4.52 (d,J=13.6 Hz, 0.56H), 4.43 (d, J=14.2 Hz, 0.46H), 1.53 (s, 3H).

(S)—N-(3-Chloro-4-cyanophenyl)-3-(5-fluoro-1H-indazol-1-yl)-2-hydroxy-2-methylpropanamide(92, 93)

Method B

Yield; 74%

MS (ESI) 370.8 [M−H]⁻

¹H NMR (400 MHz, CDCl₃) δ 8.97 (bs, 1H, NH), 7.99 (s, 0.56H), 7.95 (s,0.46H), 7.83 (d, J=2.4 Hz, 0.46H), 7.83 (d, J=2.0 Hz, 0.54H), 7.64-7.45(m, 2H), 7.39-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.16-7.11 (m, 1H), 6.63(s, OH, 0.46H), 6.04 (s, OH, 0.54H), 4.92 (d, J=13.6 Hz, 0.46H), 4.92(d, J=14.0 Hz, 0.54H), 4.50 (d, J=13.6 Hz, 0.46H), 4.40 (d, J=14.0 Hz,0.54H), 1.58 (s, 3H).

Example 5 Androgen Receptor Binding, Transactivation, and Metabolism ofIndole Based SARDs Ligand Binding Assay

Objective:

To determine SARD binding affinity to the AR-LBD.

Method:

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant AR-LBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (Kd) of [³H]mibolerone. Protein was incubated with increasingconcentrations of [³H]mibolerone with and without a high concentrationof unlabeled mibolerone at 4° C. for 18 h in order to determine totaland non-specific binding. Non-specific binding was then subtracted fromtotal binding to determine specific binding and non-linear regressionfor ligand binding curve with one site saturation to determine the Kd ofmibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻² M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using biogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as Ki.

Transactivation Assay for Wt and Mutant AR

Objective:

To determine the effect of SARDs on androgen-induced transactivation ofAR wildtype (wt) or AR carrying known AR-LBD mutants (i.e., W741L orT877A).

Method:

HEK-293 cells were plated at 125,000 cells/well of a 24 well plate inDME+5% csFBS without phenol red. Cells were transfected with 0.25 ugGRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) or CMV-hAR(W741L)or CMV-hAR(T877A) using lipofectamine transfection reagent in optiMEMmedium. Medium was changed 24 h after transfection to DME+5% csFBSwithout phenol red and treated with a dose response of various drugs(Table 1: 11-18, 20-27, 30, 31, 33, 70-74) (1 pM to 10 uM). SARDs andantagonists were treated in combination with 0.1 nM R1881. Luciferaseassay was performed 24 h after treatment on a Biotek synergy 4 platereader. Firefly luciferase values were normalized to renilla luciferasevalues. For FIG. 1A-FIG. 1C, the following variation of the method wasused:

HEK cells were plated in 24 well plates at 60,000 cells per well inDMEM+5% csFBS without phenol red. After overnight incubation, changedmedium to OptiMEM (0.25 ml). All the wells were transfected with 0.25 ugGRE-LUC, 5 ng CMV-renilla LUC, and 25 ng CMV-hAR. Twenty four hoursafter transfection, medium was replaced with 1 ml of DME+5% csFBSwithout phenol red. Twenty-four hrs after transfection, the cells weretreated with 20, 18, and 14 (FIG. 1A), 12 and 11 (FIG. 1B), 11, 27, and23 (FIG. 1C), 34-42 (FIG. 29A, FIG. 29B, FIG. 29D, FIG. 29E, FIG. 29F,FIG. 29G, FIG. 29H, FIG. 29I, FIG. 29K, FIG. 29O) and were harvested 48hrs after transfection and firefly and renilla luciferase assayperformed.

Transactivation.

HEK-293 cells were plated at 120, 000 cells per well of a 24 well platein DME+5% csFBS. The cells were transfected using Lipofectamine(Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC, 0.01 μg CMV-LUC(renilla luciferase) and 25 ng of the AR. The cells were treated 24 hrsafter transfection as indicated in the figures and the luciferase assayperformed 48 hrs after transfection. Data are represented as IC50obtained from four parameter logistics curve.

AR Degradation Using Compounds of this Invention

Objective:

To determine the efficacy and potency of AR degradation by SARDcompounds in AD1 cells, LNCaP (T877A AR) or 22RV-1 (full length AR andtruncated splice variant AR (AR-V7)) cell lines.

Method:

See Example 6 below.

Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds:

Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 m) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage (IS) of −4200 V (negativemode). Declustering potential (DP), entrance potential (EP), collisionenergy (CE), product ion mass, and cell exit potential (CXP) wereoptimized for each compound.

TABLE 1 AR Binding, Inhibition of AR Transactivation, AR Degradation andin vitro Metabolic Stability of SARDs: Transcriptional Activation (+0.1nM R1881; R1881 EC₅₀ = 0.11 nM SARD activity T_(1/2) (min) Binding Wt.W741L T877A (Figure CL_(int) Compound K_(i) (nM) IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM) Numbers) (μl/min/mg) DHT 1 — — — Bicalutamide 545.5 248.2 —557 Enzalutamide 205.2 216.3 939 331.94 ARN-509 — 297.0 1939.41 390.50ASC-J9 — 1008.0 3487.68 2288.16 11 57.8 50.9 13.68 48.47 2A, 3, 5, 6C12.35 min 56.14 mL/min/kg 11R — 351.21 — — 12 314.22 103.34 11, 14 37.2718.6 13 625.01 — 3 14 223.74 71.81 15.97 (partial) 43.4 15 >10,000 —29.79 23.28 16 489.88 2285.14 17 80.43 18 416.03 335.98 21.07 32.9 20432.69 88.03 2A, 3, 4, 11, 19.27 12 35.97 21 293.84 984.52 20.37 34.0222 419.35 126.73 36.32 19.08 23 212.49 85.10 11 22.39 30.96 24 315.84917.68 12 17.02 40.73 27 2079.94 63.69 11 13.66 50.75 30 995.23 971.7812 25.78 (UT-155 26.89 38 nM in the same exp) 31 547.27 157.41 13, 1521.77 31.84 33 >10,000 684.64 70 530.72 299.78 16 72 — 1016 32 46.5857.76 13.48 51.43 73 724.07 998.56 16 74 1399.69 720.61

The short half-lives (t_(1/2)) and high metabolic clearance (CL_(int))values in vitro of many of the compounds of this invention suggest rapidplasma clearance which could be favorable for topical treatment ofandrogenic dermatologic disorders as it would limit the risk of systemicside effects, even if the skin is penetrated.

TABLE 2 Binding Affinity of SARD Compounds of this Invention Relativebinding Compound K_(i) (nM) affinity (RBA) DHT 8.88 1.00 6.62 12 817.30.011 11 57.8 0.152 11R 333.07 0.027 14 179.77 0.049 15 663.05 0.010

FIG. 1A-FIG. 1C and FIG. 29A-FIG. 29O and Tables 1-3 show that many ofthe SARDs of this invention had higher AR binding affinity (see tables)and more potent AR antagonism in vitro (see Tables 1, 2, & 3 and figuresreferenced above and in the tables) than all the other AR antagoniststested (bicalutamide, enzalutamide, ARN-509, and ASC-J9). Furthercompound 11 retained highly potent antagonist activity in the tworesistance mutants tested (Table 1) unlike the known antiandrogenstested.

TABLE 3 AR Binding, Inhibition of AR Transactivation, AR Degradation andMetabolic Stability of SARDs SARD Activity Full S.V. Binding/Wt. Length(22RV1) Ki % inhi- % inhi- DMPK Log P (nM) bition bition (MLM) Compd(−0.4 to (DHT = IC₅₀ at at T_(1/2) ID Structure +5.6) 1 nM) (nM) 1, 10uM 10 uM Clint Enobos- arm

3.44 20.21 ~20 R-Bicalut- amide

2.57 508.84 248.2 Enzalut- amide

4.56 3641.29 216.3 ARN- 509

3.47 1452.29  0  0

2.57 87.67 —

1.86 407.08 27

3.31 2079.94 63.69 13, 89 13.66 50.75 22

3.47 419.35 126.73 54, 81 36.32 19.08 11

3.47 267.39 85.10 65-83  60-100 12.35 56.14 ) 11R

3.47 >10000 589.84 83 23

3.47 212.49 85.10  0, 100 22.39 30.96 12

3.34 314.22 103.34  43, 100 37.27 18.6  20

3.34 432.69 88.03  45, 100 78 19.27 35.97 32

3.34 46.58 57.76  0, 100 13.48 51.43 24

4.14 315.84 917.68  0 17.02 40.73 21

4.67 293.84 984.52 13 20.37 34.02 18

4.23 416.03 335.98 74, 79 47 21.07 32.9  16

3.18 489.88 2285.14 13

3.80 625.01 — 52, 86 17

3.87 80.43 545.48 0, 0 14

3.34 223.74 71.81 (partial) 1018.73 (Agonist 15.97 43.4  80

2.85 >10,000 684.64 15

2.87 >10,000 — 29.79 23.28 19

5.33 —

6.09 — 30

3.47 995.23 971.78 (UT-155 38 nM in the same exp) 25.78 26.89 31

3.95 547.27 157.41 21.77 31.84 70, 71 (mix- ture)

2.70 530.72 299.78 50 48.58 14.27

72

4.56 — 1016 73

2.86 724.07 998.56  7, 68 74

3.50 1399.69 720.61 75

2.70 >1000 973.15 14 90, 91 (mix- ture)

3.08, 3.45 806.67 851.94  0  8

33

5.14 124.66 214.66 54 22 15.43 44.94 34

4.78 132.94 See FIG. 29O 202.67 See FIG. 29O 55 41 9.131 75.91 35

3.10 155.74 See FIG. 29K 98.47 65, 80  0 36

3.10 315.32 See FIG. 29I 141.99 See FIG. 29I 71 41 11.77 58.8  37

3.10 252.58 See FIG. 29H 94.33 See FIG. 29H 81 30 38

3.10 331.79 See FIG. 29G 44.50 See FIG. 29G 68 (100 nM) 62 9.291 74.6 39

3.10 719.81 See FIG. 29F 233.8 See FIG. 29F 40 45 92, 93 (mix- ture)

2.72, 3.08 No binding See FIG. 29E 946. 84 See FIG. 29E 40 80

40

4.78 134.88 See FIG. 29D 1032.14 See FIG. 29D  0  0 41

4.98 84.32 See FIG. 29B >10000 See FIG. 269  0  0 42

5.14 86.18 See FIG. 29A 1015.12 See FIG. 29A  0  0

TABLE 4 Liver Microsome Data of Indole Based SARDs MLM HLM RLM DLM CompdID T1/2 ClInt T1/2 ClInt T1/2 ClInt T1/2 ClInt 27 13.66 50.75 22 36.3219.08 (4-F) 11 14.35 48.30 14.62 47.40 (5-F) 23 22.39 30.96 (6-F) 1237.27 18.60 (4-NO₂) 20 19.27 35.97 17.97 38.57 (5-NO₂) 32 13.48 51.43(6-NO₂) 24 17.02 40.73 (5-Br) 21 29.39 20.37 (5-I) 18 37.71 18.38(5-CF₃) 14 15.97 43.40 (5-CN) 15 29.78 23.28 (3-CO₂H) 30 25.78 26.8913.77 0.05034 70, 71 48.58 14.27 16.36 42.37 33 15.43 44.94 7.31 94.8234 9.131 75.91 15.50 58.87 38 9.291 74.6 6.611 104.9 36 11.77 58.8 12.6654.7

Example 6 Androgen Receptor Binding and Transactivation, AR Degradation,and In Vitro Metabolism of Indoline, Quinolone and Isoquinoline BasedSARDs

Ligand Binding Assay

Objective:

To determine SARDs binding affinity to the AR-LBD.

Method:

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (Kd) of [³H]mibolerone. Protein was incubated with increasingconcentrations of [³H]mibolerone with and without a high concentrationof unlabeled mibolerone at 4° C. for 18 h in order to determine totaland non-specific binding. Non-specific binding was then subtracted fromtotal binding to determine specific binding and non-linear regressionfor ligand binding curve with one site saturation to determine the Kd ofmibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻² M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BiogelHT® hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as Ki.

Transactivation Assay-Wt and Mutant AR

Objective:

To determine the effect of SARDs on androgen-induced transactivation ofAR wildtype (wt) or AR carrying known AR-LBD mutants (i.e., W741L orT877A).

Method:

HEK-293 cells were plated at 125,000 cells/well of a 24 well plate inDME+5% csFBS without phenol red. Cells were transfected with 0.25 ugGRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) or CMV-hAR(W741L)or CMV-hAR(T877A) using lipofectamine transfection reagent in optiMEMmedium. Medium was changed 24 h after transfection to DME+5% csFBSwithout phenol red and treated with a dose response of various drugs (1pM to 10 uM). SARDs and antagonists were treated in combination with 0.1nM R1881. Luciferase assay was performed 24 h after treatment on aBiotek synergy 4 plate reader. Firefly luciferase values were normalizedto renilla luciferase values. (Table 3)

Plasmid Constructs and Transient Transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ obtained from four parameter logistics curve.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using biogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

LNCaP Gene Expression Assay.

Method:

LNCaP cells were plated at 15,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Forty-eight hours after plating, cellswere treated with a dose response of SARDs. Twenty four hours aftertreatment, RNA was isolated using cells-to-ct reagent, cDNA synthesized,and expression of various genes was measured by realtime rtPCR (ABI7900) using taqman primers and probes. Gene expression results werenormalized to GAPDH.

LNCaP Growth Assay.

Method:

LNCaP cells were plated at 10,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method:

LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 uM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method:

22RV1 and D567es cells expressing AR splice variants were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 Growth and Gene Expression.

Methods:

Cell growth was evaluated as described before by SRB assay. Cells wereplated in 96 well plate in full serum and treated for 6 days with mediumchange after day 3. Gene expression studies were performed in 22RV1cells plated in 96 well plate at 10,000 cells/well in RPMI+10% FBS.Twenty four hours after plating, cells were treated for 3 days and geneexpression studies were performed as described before.

Determination of Metabolic Stability (In Vitro CL_(int)) of TestCompounds:

Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage (IS) of −4200 V (negativemode). Declustering potential (DP), entrance potential (EP), collisionenergy (CE), product ion mass, and cell exit potential (CXP) wereoptimized for each compound.

TABLE 5 AR Binding, Inhibition of AR Transactivation, AR Degradation andin vitro Metabolic Stability of SARDs DMPK SARD activity (MLM)Binding/Wt. (estimated T_(1/2) (min) Ki IC₅₀ median effect CL_(int) CompID Structure (nM) (nM) (nM) (μl/min/mg) Enobosarm

8.385 ~20 R-Bicalutamide

211.12 248.2 — Enzalutamide

678.9 216.3 — ARN-509

>1000 + 100

23.17 34.16 530.95 10-100 (FIG. 18 & FIG. 19) 66.87 min 10.38 μl/min/mg101

83.1 58.96 100-500 (FIG. 25) 25.06 min 27.67 μl/min/mg 102

126.8 26.28 100-500 (FIG. 19 & FIG. 21) 55.14 min 12.57 μl/min/mg 103

382.44 126.13 10000 (FIG. 22) 104

326.14 130.37 10-100 (FIG. 22) 29.16 min 23.77 μl/min/mg 105

273.04 38.74 (FIG. 25) 106

489.95 36.45 (FIG. 25) 130

1530.58 420.07 1000-5000 (FIGS. 19, FIG. 20, FIG. 23 & FIG. 24) 161.7min 4.286 μl/min/mg 134

201.98 573.98 5000-10000 (FIG. 7A and FIG. 7B 38.25 min 18.12 μl/min/mg135

3112.73 867.48 10-100 nM (FIG. 21) 15.25 min 45.45 μl/min/mg 131

398.63 1002.73 — 25.42 min 27.27 μl/min/mg 107

67.65 74.65 (FIG. 25) 108

114.84 100.55 (FIG. 25)The short half-lives (t_(1/2)) and high metabolic clearance (CL_(int))values in vitro of some of the compounds of this invention suggest rapidplasma clearance for those compounds which could be favorable fortopical treatment of androgenic dermatologic disorders as it would limitthe risk of systemic side effects, even if the skin is penetrated. Othercompounds demonstrate relatively long half-lives and low metabolicclearances values in vitro suggesting that these compounds may be ableto achieve systemic exposures necessary to have systemic antiandrogeneffects such as would be necessary to treat prostate cancer.

TABLE 6 AR Binding, Inhibition of AR Transactivation, AR Degradation andMetabolic Stability of SARDs SARD Activity Full S.V. Binding/Wt. Length(22RV1) Ki % inhi- % inhi- DMPK Log P (nM) bition bition (MLM) Compd(−0.4 to (DHT = IC₅₀ at at T_(1/2) ID Structure +5.6) 1 nM) (nM) 1, 10uM 10 uM Clint Enobos- arm

3.44 20.21 ~20 R-Bicalut- amide

2.57 508.84 248.2 Enzalut- amide

4.56 3641.29 216.3 ARN- 509

3.47 1452.29  0  0 DJ-I- 223

2.57 87.67 — DJ-VI- 5E

1.86 407.08 100

4.62 197.67 530.95 60 41 66.87 10.38 101

3.95 169.86 58.96 61  5 25.06 27.67 102

3.95 807.22 137.04 95 63 55.14 12.57 103

3.59 382.44 126.13 58 71 15 46.22 104

3.59 326.14 130.37 47, 69 15 29.16 23.77 105

3.95 273.04 38.74 60 30 105 106

3.59 489.95 36.45 99 12 107

4.51 67.65 Agonist 30-48  0 108

4.11 114.84 100.55 54 36 109

3.80 >1000 142.13 84 45 110

3.75 251.94 31.71 79 40 114

4.25 204.36 See FIG. 26L 834.68 See FIG. 26L 37, 84  0 17.35 39.36 115

5.27 71.48 See FIG. 26I 244.43 See FIG. 26I 93 (100 nM) 90 21.37 32.44130

4.28 1530.58 420.07 70, 78 65 161.7 4.286 131

3.61 398.63 1002.73 24 25.42 27.27 132

3.61 353.19 See FIG. 26C 978.91 See FIG. 26C  0 60 134

5.04 201.98 573.98 38.25 18.12 135

4.37 3112.73 867.48 21 15.25 45.45

TABLE 7 Liver Microsome Data of Indoline Based SARDs MLM HLM RLM DLMCompd ID T1/2 ClInt T1/2 ClInt T1/2 ClInt T1/2 ClInt 102 55.14 0.01257(5F- indoline) 100 66.87 10.38 64.84 0.01069 (5Br- indoline) 102 28.1324.64 17.71 39.13 101 25.06 27.67 135 15.21 45.57 7.54 91.94 131 25.4227.27 6.553 105.8 104 29.16 23.77 24.7 28.06 3.33 208 49.44 14 103 1546.22 20.07 34.54 2.09 330 42.8 16.19 114 17.35 39.96 6.084 113.9 11521.37 32.44 11.77 58.87

Example-7 AR Degradation Using Compounds of this Invention (Indoles)

LNCaP Gene Expression Assay

Objective:

To determine the effect of SARDs on AR-target gene expression in LNCaPcells.

Method:

LNCaP cells were plated at 15,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Forty-eight hours after plating, cellswere treated with a dose response of SARDs. Sixteen-twenty four hoursafter treatment, RNA was isolated using cells-to-ct reagent, cDNAsynthesized, and expression of various genes was measured by realtimertPCR (ABI 7900) using taqman primers and probes. Gene expressionresults were normalized to GAPDH.

LNCaP Growth Assay

Objective:

To determine the effect of SARDs on LNCaP cell growth.

Method:

LNCaP cells were plated at 10,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP Degradation Assay

Objective:

To determine the effect of SARDs on AR expression in LNCaP cells.

Method:

LNCaP cells were plated at 750,000-1,000,000 cells/well of a 6 wellplate in growth medium (RPMI+10% FBS). Twenty four hours after plating,medium was changed to RPMI+1% csFBS without phenol red and maintained inthis medium for 2 days. Medium was again changed to RPMI+1% csFBSwithout phenol red and cells were treated with SARDs (1 nM to 10 uM) incombination with 0.1 nM R1881. After 16-20 h of treatment, cells werewashed with cold PBS and harvested. Protein was extracted usingsalt-containing lysis buffer with three free-thaw cycles. Proteinconcentration was estimated and five microgram of total protein wasloaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane.The membrane was probed with AR N-20 antibody from SantaCruz and actinantibody from Sigma.

22RV-1 Degradation Assay

Objective:

To determine the effect of SARDs on AR full length and splice variantexpression in 22RV-1 cells.

Method:

22RV-1 cells were plated at 750,000-1,000,000 cells/well of a 6 wellplate in growth medium (RPMI+10% FBS). Twenty four hours after plating,medium was changed and treated. After 16-20 h of treatment, cells werewashed with cold PBS and harvested. Protein was extracted usingsalt-containing lysis buffer with three free-thaw cycles. Proteinconcentration was estimated and five microgram of total protein wasloaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane.The membrane was probed with AR N-20 antibody from SantaCruz and actinantibody from Sigma.

FIG. 2A presents degradation in LNCaP cells using 11 and 20. LNCaP cellswere plated in 6 well plates at 1 million cells/well. The cells weremaintained in serum free condition for 3 days. The cells were treated asindicated in the figure, harvested, protein extracted, and Westernblotted for AR. 11 demonstrated selective degradation of AR (i.e., SARDactivity) in nM range, i.e., at concentrations comparable to itsantagonist IC₅₀ value. LNCaP cells are known to express the AR mutantT877A, demonstrating the ability to degrade resistance conferring mutantandrogen receptors.

FIG. 2B presents the effect of AR antagonists and SARDs on LNCaP cellgrowth: LNCaP cells were plated in 96 well plates at 10,000 cells/wellin RPMI+1% csFBS without phenol red. Cells were treated as indicated inthe figure in combination with 0.1 nM R1881 for 6 days with mediumchange on day 3. At the end of 6 days, the cells were fixed and stainedwith sulphorhodamine blue stain. 11 demonstrated more potentanti-proliferative activity in LNCaP cells at 1 and 10 μM when comparedto enzalutamide and ARN-509.

FIG. 3 presents AR-V7 degradation (PC3-AR-V7 cells) using 11, 12 and 20at 1 μM and 10 μM. PC-3 prostate cancer cells were serum stablytransfected with a lentivirus construct for AR-V7. Once the stable cellswere selected, the cells were plated in 6 well plates at 1 millioncells/well. The cells were treated as indicated in the figure andWestern blot performed for AR and actin. The results show that the SARDshave the potential to degrade the truncated version of AR, whileenzalutamide or ARN-509 had no effect of the AR-V7 expression.

SARD Compounds of this Invention Degrade AR-SV in 22RV-1 Cells

FIG. 4—22RV-1 Western blot: 22RV-1 cells were plated in 6 well plate at1-1.5 million cells/well in growth medium (RPMI+10% FBS). Next day,medium was changed and treated with vehicle or a dose response of 20.After overnight treatment (12-16 hrs), cells were washed in ice cold PBSand harvested by scrapping in 1 mL PBS. Cells were pelleted, proteinextracted, quantified using BCA assay, and equal quantity of protein wasfractionated on a SDS-PAGE. The proteins were transferred to nylonmembrane and Western blotted with AR antibody (N20 from SCBT) and actinantibody. 20 was capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-SV) in 22RV-1 cells, suggesting that SARDsmay be able to overcome AR-V7 dependent prostate cancers (e.g., CRPC).11 degraded AR-FL but not actin in LNCaP cells (FIG. 5) and AR-FL andAR-SV in 22RV-1 cells (FIG. 6A-FIG. 6C). FIG. 6A-FIG. 6C shows that 11degraded AR-FL and AR-V7 at nM concentrations (FIG. 6C) whereas ARN-509did not degrade either (FIG. 6B). Although ASC-J9 did exhibit somedegradation in the nM range, μM concentrations failed to degrade AR(FIG. 6A). 11 also inhibited AR-dependent gene expression in LNCaPcells, transactivation of AR in 22RV-1 cells and cellular growth in boththe cell types (Table 8 and Table 9). Cumulatively, these observationssuggest that SARDs of this invention may be useful in prostate cancersthat are dependent on mutant ARs, AR-FL and/or AR-SV.

FIG. 11 presents degradation in LNCaP cells using 27, 20, 12, 23 and 32.LNCaP cells were plated in 6 well plates at 1 million cells/well. Thecells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. All SARDs demonstrated selective degradationof AR (i.e., SARD activity) at concentrations comparable to theirantagonist IC₅₀ values. LNCaP cells are known to express the AR mutantT877A, demonstrating the ability to degrade antiandrogen resistanceconferring mutant androgen receptors (i.e., advanced prostate cancersand CRPC).

FIG. 12: 22RV-1 Western blot: 22RV-1 cells were plated in 6 well platesat 1-1.5 million cells/well in growth medium (RPMI+10% FBS). Next day,medium was changed and treated with vehicle or a dose response of 20, 24and 30. After overnight treatment (12-16 hrs), cells were washed in icecold PBS and harvested by scrapping in 1 mL PBS. Cells were pelleted,protein extracted, quantified using BCA assay, and equal quantity wasfractionated on a SDS-PAGE. The proteins were transferred to nylonmembrane and Western blotted with AR antibody (N20 from SCBT) and actinantibody. 20, 24 and 30 were capable of degrading full length androgenreceptor (AR-FL) and truncated AR (AR-V7) in 22RV-1 cells, suggestingthat SARDs may be able to overcome AR-V7 dependent prostate cancers(i.e., CRPC).

FIG. 13 presents degradation in LNCaP cells and 22RV-1 cells using 31vs. galeterone. The experiments were performed by the methods citedabove. A dose response of SARD 31 demonstrated the ability to degradefull length AR in LNCaP and 22RV-1 cell lines, whereas galeterone wasnot able to substantially degrade AR in either cell line.

FIG. 14 presents degradation in LNCaP cells using 12 vs. ARN-509. 12 andARN-509 both demonstrated the ability to degrade AR in LNCaP cells,however 12 demonstrated activity at 1 μM whereas ARN-509 onlydemonstrated activity at 10 μM.

FIG. 15 presents degradation in 22RV-1 cells using 31. 31 demonstratedthe ability to degrade AR-FL and AR-SV in 22RV-1 cells at 10 μMaffecting actin levels (i.e., selective AR degradation).

FIG. 16 presents degradation in LNCaP cells using 70 and 73. Using themethods described in the legend for FIG. 11 (LNCaP), SARD activity for70 and 73 was demonstrated at concentrations as low as 100 nM. Thisdemonstrates that benzimidazoles of this invention also demonstratepotent SARD activity.

These SARD activity demonstrations suggest the compounds of thisinvention are able to degrade a variety of AR variants, and hence shouldprovide the ability to inhibit the AR-axis activity whether it isandrogen-dependent or androgen-independent. Degradation of the ARremoves the possibility of promiscuous activation of mutant ARs,activation by intracellular processes such as signal transduction andkinase activation, etc.; and suggests that the SARDs should also degradethe polyQ polymorphisms in hyperandrogenic dermatologic disorders(shortened polyQ) or Kennedy's disease (extended polyQ), providing arationale for treating either type of disease by destroying the AR inthe affected tissues (skin and neuromuscular system, respectively).

TABLE 8 Inhibition of Growth and Gene Expression of LNCaP PCa Cells GeneExpression IC₅₀ (nM) Growth Compound PSA TMPRSS2 IC₅₀ (nM) Bicalutamide783.7 831.4 Enzalutamide 384.4 72.3 872 Compound 11 5.0 13.1 271 ARN-509169.7 517.1 994 ASC-J9 >10,000 >10,000 1064

TABLE 9 Effects of SARDs on AR-transactivation and growth of 22RV-1Transactivation Growth Compound IC₅₀ (nM) IC₅₀ (nM) Bicalutamide3133.52 >10,000 Enzalutamide 101.87 >10,000 Compound 11 420.62 1041ARN-509 64.54 >10,000 ASC-J9 1026.91 >10,000

Example 8 AR Degradation Using Indoline, Quinoline, or Isoquinoline SARDCompounds of this Invention

Plasmid Constructs and Transient Transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ obtained from four parameter logistics curve.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using biogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

LNCaP Gene Expression Assay.

Method:

LNCaP cells were plated at 15,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Forty-eight hours after plating, cellswere treated with a dose response of SARDs. Twenty four hours aftertreatment, RNA was isolated using cells-to-ct reagent, cDNA synthesized,and expression of various genes was measured by realtime rtPCR (ABI7900) using taqman primers and probes. Gene expression results werenormalized to GAPDH.

LNCaP Growth Assay.

Method:

LNCaP cells were plated at 10,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method:

LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 uM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method:

22RV1 and D567es cells expressing AR splice variants were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 growth and gene expression.

Methods:

Cell growth was evaluated as described before by SRB assay. Cells wereplated in 96 well plate in full serum and treated for 6 days with mediumchange after day 3. Gene expression studies were performed in 22RV1cells plated in 96 well plate at 10,000 cells/well in RPMI+10% FBS.Twenty four hours after plating, cells were treated for 3 days and geneexpression studies were performed as described before.

Results:

FIG. 18 presents degradation in LNCaP cells using 100 compared toARN-509. LNCaP cells were plated in 6 well plates at 1 millioncells/well. The cells were maintained in serum free conditions for 3days. The cells were treated as indicated in the figure,harvestedprotein extracted, and Western blotted for AR. 100 demonstratedselective degradation of AR (i.e., SARD activity) in the nM range, i.e.,at concentrations comparable to its antagonist IC₅₀ value whereasARN-509 only demonstrated SARD activity at the highest concentrationtested. LNCaP cells are known to express the AR mutant T877A,demonstrating the ability of compounds of this invention to degradeantiandrogen resistance conferring mutant androgen receptors.

FIG. 19 demonstrates via Western blot that 100, 102, and 130 degradedAR-FL and AR-SV in 22RV-1 cells. 22RV-1 cells were plated in 6 wellplate at 1-1.5 million cells/well in growth medium (RPMI+10% FBS). Nextday, medium was changed and treated with vehicle or a dose response of100, 102, and 130. After overnight treatment (12-16 hrs), cells werewashed in ice cold PBS and harvested by scrapping in 1 mL PBS. Cellswere pelleted, protein extracted, quantified using BCA assay, and equalquantity of protein was fractionated on a SDS-PAGE. The proteins weretransferred to nylon membrane and Western blotted with AR antibody (N20from SCBT) and actin antibody. 87, 43, and 35 were capable of degradingfull length androgen receptor (AR-FL) and truncated AR (AR-SV) in 22RV-1cells, suggesting that SARDs may be able to overcome AR-V7 dependentprostate cancers.

FIG. 20 presents degradation in 22RV-1 cells using 130 vs. galeterone.Using the methods described in the legend for FIG. 18 (22RV-1), 130 wascompared to galeterone (a clinical lead SARD). 130 demonstrated SARDactivity in 22RV-1 (growth dependent on AR-SV, an AR variant lacking aLBD) cells which was comparable to galeterone.

FIG. 21 presents degradation in LNCaP cells using 135 and 102. Using themethods described in the legend for FIG. 1A-FIG. 1C, SARD activities for135 and 102 was demonstrated. These compounds partially and fullydegraded mutant AR (T877A), suggesting that SARDs such as these may beuseful in advanced prostate cancer and/or CRPC.

FIG. 22 presents degradation in LNCaP cells and 22RV-1 cells using 103and 104. Using the methods described in the legends for FIG. 1A-FIG. 1C(LNCaP) and FIG. 2A-FIG. 2B (22RV-1), 103 and 104 demonstrated SARDactivity in both LNCaP (mutant AR harboring T877A mutation) and 22RV-1(growth dependent on AR-SV lacking a LBD) cell.

FIG. 23 presents degradation in 22RV-1 cells using 130. Using themethods described in the legend for FIG. 19, compound 130 demonstratedSARD activity at least at the 10 μM concentration.

FIG. 24 presents degradation in 22RV-1 cells using 134 and 130. Usingthe methods described in the legend for FIG. 19, compounds 134 and 130each demonstrated SARD activity at least at the 10 μM concentration.

FIG. 25 presents degradation in LNCaPcells using −101, 105, 106, 107 and108 LNCaP cells plated in 6 well plates at 500,000 cells/well weremaintained in RPMI+1% csFBS without phenol red for 2 days. Cells weretreated as indicated above in combination with 0.1 nM R1881 for 24 hrs.Cells were harvested 24 hrs after treatment, protein extracted, Westernblotted with AR antibody (Santacruz AR N-20) and actin antibody. 101,105, 106, 107 and 108 each demonstrated the ability to degrade the AR inthe nM range.

These SARD activity demonstrations suggest the compounds of thisinvention are able to degrade a variety of AR variants, and hence shouldprovide the ability to inhibit the AR-axis activity whether it isandrogen-dependent or androgen-independent. Degradation of the ARremoves the possibility of promiscuous activation of mutant ARs,activation by intracellular processes such as signal transduction andkinase activation, etc.; and suggests that the SARDs should also degradethe polyQ polymorphisms in hyperandrogenic dermatologic disorders(shortened polyQ) or Kennedy's disease (extended polyQ), providing arationale for treating either type of diseases by destroying the AR inthe affected tissues (skin and neuromuscular system, respectively).Further, a spectrum of in vitro metabolic stabilities were observedsuggesting the possibility of either topical administration (shorthalf-life such that systemic exposure are limited) or systemic (e.g.,oral; requires relatively long half-lives) administration.

Example 9 SARDs (Indoles) Inhibit Ligand Independent AR Transcription

Compound 11 inhibited transactivation in the AR-NTD-DBD-hinge (A/BCD) ARconstruct which lacks the ligand binding domain (FIG. 7A-FIG. 7D). (FIG.7A.) AR A/BCD increased GRE-LUC reporter activity. AR A/BCD constructthat lacks the ligand binding domain or empty vector was transfectedinto HEK-293 cells along with GRE-LUC and CMV-renilla LUC. Forty eighthours after transfection cells were harvested and luciferase assayperformed. (FIG. 7B.-FIG. 7D.) AR A/BCD activity was inhibited by 11. ARA/BCD construct that lacks the ligand binding domain (LBD) wastransfected along with GRE-LUC and CMV-LUC. Cells were treated 24 hrsafter transfection as indicated in the figure and luciferase assayperformed 48 hrs after transfection. 11 (a SARD) inhibited the activityof construct lacking LBD confirming the binding to an alternate site inaddition to the LBD. Non-SARD antagonists ARN-509 and enzalutamide didnot inhibit the activity of this AR construct lacking the LBD,suggesting that SARDs can inhibit ligand independent AR activity via analternative binding and degradation domain (BDD) located outside of theLBD.

Example 10 Comparison of SARDs and Clinical Candidates in Binding andTransactivation

Plasmid Constructs and Transient Transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 mg GRE-LUC,0.02 mg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 h after transfection as indicated in the figures and theluciferase assay performed 48 h after transfection. Data are representedas IC₅₀ obtained from a four parameter logistics curve.

FIG. 8A presents the data comparing 11, 12, and 14 with galeterone,EPI-001, and enzalutamide, in the transactivation study. FIG. 8B showsthe data comparing 11 with galeterone and enzalutamide in thetransactivation study. The results show that the SARD compounds of thepresent invention were several more potent than galeterone andenzalutamide in inhibition of DHT activated AR transactivation in vitro.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant AR-LBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(D)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(D) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR-LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BiogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i). Table 10 shows that the SARD compounds of thepresent invention are at least approximately 8-10 fold more tightlybound than galeterone and enzalutamide in AR binding assay studies.

TABLE 10 Binding Assay Results Compound Binding (Ki) nM 11 62.7 14 47.912 72.9 Galeterone 922.8 Enzalutamide 678.9 EPI-001 Does Not Bind

Example 11 Compound 11 Inhibits Tumor Growth of an Aggressive ProstateCancer Expressing AR Splice Variant

Xenograft Experiment.

NOD SCID gamma (NSG) mice (n=8-10) were housed as five animals per cageand were allowed free access to tap water and commercial rat chow(Harlan Teklad 22/5 rodent diet—8640). Cell line xenografts wereperformed as previously published (Narayanan et al., 2010; Yepuru etal., 2013). LNCaP tumors were grown in intact mice, while 22RV-1 tumorswere grown in castrated mice. Once tumor size reached 100 mm³, theanimals were randomized and treated with vehicle control (polyethyleneglycol: DMSO 9:1 ratio) or 11 (50 mg/kg/day s.c.). Tumor volume wascalculated using the formula length*width*width*0.5236. At the end ofthe experiment, animals were sacrificed, tumors were collected, weighed,and stored for further analysis. Blood was collected, serum separated,and serum PSA was measured using ELISA.

All experiments were performed thrice and each in vitro experiment wasperformed in triplicate. Statistical analysis was performed usingJMP-Pro software (SAS; Cary, N.C.). Experiments containing only twogroups were analyzed by simple t-test, while experiments containing morethan two groups were analyzed by One Way ANOVA, followed by appropriatepost-hoc test.

22RV-1 Xenograft Studies with Compound 11:

Since 11 degraded both AR-FL and AR-SV in LNCaP and 22RV-1 cells, themolecule was evaluated in 22RV-1 and LNCaP xenograft studies. FIG.9A-FIG. 9B show that compound 11 inhibited tumor growth of an aggressiveprostate cancer expressing AR splice variant. 22RV-1 is a highlyaggressive tumor model that is unresponsive to any currenty availabletratements. A SARD compound of the present invention, 11, restricted itsgrowth by approximately 50%. No side-effects were observed in the 3-4weeks study. FIG. 9C demonstrated that 11 degraded both AR-FL and AR-V7in the 22RV-1 xenografts whereas enzalutamide demonstrated nodegradation of either AR in these xenografts. FIG. 9D demonstrated that11 but not enzalutamide suppressed serum PSA in xenograft bearinganimals, demonstrating that 11 suppressed AR gene expression in thesetumors. This demonstrated that 11 but not enzalutamide can overcome theantiandrogen resistance present in 22CV-1 cells (e.g., AR-V7 dependentgrowth) by degrading the AR-V7, resulting in significantly suppressingandrogenic tone in these tumors. This provide a proof-of-concept thatSARDs such as 11 would be of clinical benefit to CRPC patients,particularly if systemic exposures could be improved.

FIG. 10A-FIG. 10C show that 11 inhibited LNCaP tumor xenograft growth.As shown in FIG. 10C, the serum PSA level was inhibited by >75%.

Example 12 SARDs Bind to the AR-AF1

There are two tryptophan residues and up to 12 tyrosine residues in theAF1 of the AR. This has allowed the study of the folding properties ofthis domain using intrinsic steady state fluorescence emission spectra.Excitation at 287 nm excites both tyrosine and tryptophan residues. Theemission maximum (λmax) for the tryptophan is sensitive to the exposureto solvent. In the presence of the natural osmolyte TMAO there is acharacteristic ‘blue shift’ consistent with the tryptophan residuesbeing less solvent exposed and a loss of the shoulder (˜307 nm) fortyrosine as there is increased energy transfer to tryptophan as thepolypeptide folds. To test if the compounds (enobosarm (negativecontrol), and 17) interact with AF-1 and/or alter the folding of thisdomain the steady state fluorescence was measured for each compound withAR-AF1 alone or the presence of TMAO (3 M) or urea (4 or 6 M). 1 μM ofAR-AF1 and 5 μM of the individual compounds were used, and preincubatedfor at least 30 minutes prior to measuring the emission spectra. Theemission spectra were all corrected for buffer alone or buffer withTMAO/urea/compounds as necessary. FIG. 17A-FIG. 17C presents biophysicaldata that suggests that SARDs bind to the N-terminal domain of the AR(in addition to the LBD in the C-terminus). FIG. 17A: Dose-dependentshift in the fluorescence intensity by 11 when incubated with AR AF-1.The fluorescence shoulder observed at 307 nm, which corresponds totyrosine residues in the AF-1, is shifted by 11. The overallfluorescence is also markedly altered by 11. FIG. 17C: Data shown in theleft panel was plotted as difference in fluorescence between control and11 treated samples (fluorescence in the absence of compound—fluorescencein the presence of compound), a dose dependent increase was observed inthe presence of 11.

Based on half-maximum saturation for the change in fluorescence signal(at λmax 242 nm), the binding constant to AR-AF1 was calculated to be ofK_(D)=1.34±0.32 μM (n=3, mean±SEM).

1 μM AR-AF1 was pre-incubated without or with increasing concentrationsof compound 11 (up to 15 μM) and steady-state fluorescence emission,after excitation at 287 nm, measured from 300 to 400 nm. Data wasanalysed as described by Epps et al (1999) J. Pharm 51, 41-48, Rawel etal (2006) Mol. Nutr. Food Res. 50, 705-713 and Wang et al (2011) Mol.Endcor. 25, 2041-2053 which are hereby incorporated by reference.

Example 13 Androgen Receptor Binding and Transactivation of CarbazoleBased SARDs Ligand Binding Assay

Objective:

To determine SARDs binding affinity to the AR-LBD.

Method:

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (Kd) of [³H]mibolerone. Protein was incubated with increasingconcentrations of [³H]mibolerone with and without a high concentrationof unlabeled mibolerone at 4° C. for 18 h in order to determine totaland non-specific binding. Non-specific binding was then subtracted fromtotal binding to determine specific binding and non-linear regressionfor ligand binding curve with one site saturation to determine the Kd ofmibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻² M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using BiogelHT® hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as Ki (Table 1).

Transactivation Assay for Wt and Mutant AR

Objective:

To determine the effect of SARDs on androgen-induced transactivation ofAR wildtype (wt) or AR carrying known AR-LB mutants (i.e., W741L orT877A).

Method:

HEK-293 cells were plated at 125,000 cells/well of a 24 well plate inDME+5% csFBS without phenol red. Cells were transfected with 0.25 ugGRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR(wt) or CMV-hAR(W741L)or CMV-hAR(T877A) using lipofectamine transfection reagent in optiMEMmedium. Medium was changed 24 h after transfection to DME+5% csFBSwithout phenol red and treated with a dose response of various drugs(Table 11: compounds 200-205) (1 pM to 10 uM). SARDs and antagonistswere treated in combination with 0.1 nM R1881. Luciferase assay wasperformed 24 h after treatment on a Biotek synergy 4 plate reader.Firefly luciferase values were normalized to renilla luciferase values.

Transactivation Assay-Wt and Mutant AR

Objective:

To determine the effect of SARDs on androgen-induced transactivation ofAR carrying known AR-LBD mutants.

Method:

HEK-293 cells were plated at 125,000 cells/well of a 24 well plate inDME+5% csFBS without phenol red. Cells were transfected with 0.25 ugGRE-LUC, 10 ng CMV-renilla LUC, and 50 ng CMV-hAR/W741L-AR/T877A-ARusing lipofectamine transfection reagent in optiMEM medium. Medium waschanged 24 h after transfection to DME+5% csFBS without phenol red andtreated with a dose response of various drugs (1 pM to 10 uM). SARDs andantagonists were treated in combination with 0.1 nM R1881. Luciferaseassay was performed 24 h after treatment on a Biotek synergy 4 platereader. Firefly luciferase values were normalized to renilla luciferasevalues. (Table 11)

AR Degradation Using Compounds of this Invention

Determination of metabolic stability (in vitro CL_(int)) of testcompounds:

Phase I Metabolism

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes) 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were included. From % PCR (% ParentCompound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin was included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™, 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage (IS) of −4200 V (negativemode). Declustering potential (DP), entrance potential (EP), collisionenergy (CE), product ion mass, and cell exit potential (CXP) wereoptimized for each compound.

TABLE 11 AR Binding, Inhibition of AR Transactivation, AR degradationand in vitro metabolic stability of SARDs: Transcriptional Activation(+0.1 nM R1881; T_(1/2) (min) R1881 EC₅₀ = 0.11 nM Com- Binding Wt.W741L T877A CL_(int) pound K_(i) (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)(μl/min/mg) DHT 1 — — — R- 545.5 248.2 — 557 Bicaluta- mide Enzaluta-205.2 216.3 939 331.94 mide ARN- — 297.0 1939.41 390.50 509 ASC-J9 —1008.0 3487.68 2288.16 200 728.59 871.21 41.77 min 16.6 mL/min/kg 201506.94 237.91 89.68 min 7.729 mL/min/kg 202The relatively long half-lives (t_(1/2)) and low metabolic clearance(CL_(int)) value in vitro compounds 200-202 of this invention suggestthe possibilities oral bioavailability and stability in serum whichwould be favorable for systemic treatment of diseases of this inventionsuch as prostate cancer, breast cancer, Kennedy's disease, and variousandrogen-dependent diseases.

TABLE 12 AR Binding, Inhibition of AR Transactivation, AR Degradationand in vitro Metabolic Stability of SARDs SARD Activity Full S.V.Binding/Wt. Length (22RV1) Ki % inhi- % inhi- DMPK Log P (nM) bitionbition (MLM) Compd (−0.4 to (DHT = IC₅₀ at at T_(1/2) ID Structure +5.6)1 nM) (nM) 1, 10 uM 10 uM Clint Enobos- arm

3.44 20.21 ~20 R-Bicalut- amide

2.57 508.84 248.2 Enzalut- amide

4.56 3641.29 216.3 ARN- 509

3.47 1452.29  0  0

2.57 87.67 —

1.86 407.08 200

4.36 728.59 871.21 48 60 41.77 16.6 201

4.40 506.94 237.91 33 89.68 7.729 202

4.52 193.80 991.15 20 29 39.94 17.35 203

4.16 248.54 1242.96 38  0 204

4.68 809.64 See FIG. 29M 1025.41 See FIG. 29M 51 205

4.00 90.68 See FIG 29K 1079.11 See FIG 29K 19, 87 87

TABLE 13 Liver Microsome Data. MLM HLM RLM DLM Compd ID T1/2 ClInt T1/2ClInt T1/2 ClInt T1/2 ClInt 200 95.9 0.72 (5-carbazole) 201 89.68 7.72961.38 0.01129 202 39.94 17.35 14.28 48.54

Example 14 AR Degradation Using Compounds of this Invention LNCaPDegradation Assay

Objective:

To determine the effect of SARDs on AR expression in LNCaP cells.Plasmid constructs and transient transfection.

Human AR cloned into CMV vector backbone was used for thetransactivation study. HEK-293 cells were plated at 120,000 cells perwell of a 24 well plate in DME+5% csFBS. The cells were transfectedusing Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC,0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR. The cells weretreated 24 hrs after transfection as indicated in the figures and theluciferase assay performed 48 hrs after transfection. Data arerepresented as IC₅₀ obtained from four parameter logistics curve.

Ligand Binding Assay.

hAR-LBD (633-919) was cloned into pGex4t.1. Large scale GST-taggedAR-LBD was prepared and purified using a GST column. Recombinant ARLBDwas combined with [³H]mibolerone (PerkinElmer, Waltham, Mass.) in bufferA (10 mM Tris, pH 7.4, 1.5 mM disodium EDTA, 0.25 M sucrose, 10 mMsodium molybdate, 1 mM PMSF) to determine the equilibrium dissociationconstant (K_(d)) of [³H]mibolerone. Protein was incubated withincreasing concentrations of [³H]mibolerone with and without a highconcentration of unlabeled mibolerone at 4° C. for 18 h in order todetermine total and non-specific binding. Non-specific binding was thensubtracted from total binding to determine specific binding andnon-linear regression for ligand binding curve with one site saturationto determine the K_(d) of mibolerone.

Increasing concentrations of SARDs or DHT (range: 10⁻¹² to 10⁻⁴ M) wereincubated with [³H]mibolerone and AR LBD using the conditions describedabove. Following incubation, the ligand bound AR-LBD complex wasisolated using biogelHT hydroxyapatite, washed and counted in ascintillation counter after adding scintillation cocktail. Values areexpressed as K_(i).

LNCaP Gene Expression Assay.

Method:

LNCaP cells were plated at 15,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Forty-eight hours after plating, cellswere treated with a dose response of SARDs. Twenty four hours aftertreatment, RNA was isolated using cells-to-ct reagent, cDNA synthesized,and expression of various genes was measured by realtime rtPCR (ABI7900) using taqman primers and probes. Gene expression results werenormalized to GAPDH.

LNCaP Growth Assay.

Method:

LNCaP cells were plated at 10,000 cells/well of a 96 well plate inRPMI+1% csFBS without phenol red. Cells were treated with a doseresponse of SARDs. Three days after treatment, cells were treated again.Six days after treatment, cells were fixed and cell viability wasmeasured by SRB assay.

LNCaP or AD1 Degradation.

Method:

LNCaP or AD1 cells expressing full length AR were plated at750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed toRPMI+1% csFBS without phenol red and maintained in this medium for 2days. Medium was again changed to RPMI+1% csFBS without phenol red andcells were treated with SARDs (1 nM to 10 uM) in combination with 0.1 nMR1881. After 24 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 and D567es Degradation.

Method: 22RV1 and D567es cells expressing AR splice variants were platedat 750,000-1,000,000 cells/well of a 6 well plate in growth medium(RPMI+10% FBS). Twenty four hours after plating, medium was changed andtreated. After 24-30 h of treatment, cells were washed with cold PBS andharvested. Protein was extracted using salt-containing lysis buffer withthree free-thaw cycles. Protein concentration was estimated and fivemicrogram of total protein was loaded on a SDS-PAGE, fractionated, andtransferred to a PVDF membrane. The membrane was probed with AR N-20antibody from SantaCruz and actin antibody from Sigma.

22RV1 Growth and Gene Expression.

Methods:

Cell growth was evaluated as described before by SRB assay. Cells wereplated in 96 well plate in full serum and treated for 6 days with mediumchange after day 3. Gene expression studies were performed in 22RV1cells plated in 96 well plate at 10,000 cells/well in RPMI+10% FBS.Twenty four hours after plating, cells were treated for 3 days and geneexpression studies were performed as described before.

Results:

FIG. 26 presents AR degradation by 1 vs. ARN-509 in LNCaP cells. Westernblot analysis by the method described above demonstrated the ability of200 to degrade a mutant AR (i.e., T877A) at 100 nM and 10 μM in LNCaPcells whereas ARN-509 only degraded at 10 μM, suggesting that SARDs suchas 200 will have clinical utility in prostate cancers including thosewhose growth is driven by antiandrogen resistance-conferring mutant AR's(i.e., advanced prostate cancers and CRPC).

FIG. 27 and FIG. 28 present AR and AR-V7 degradation by 200 and 201 in22RV-1 cells. 200 was capable of degrading full length androgen receptor(AR-FL) and truncated AR (AR-V7) in 22RV-1 cells, suggesting that SARDsmay be able to overcome AR-V7 dependent prostate cancers (i.e., CRPC).By comparison, 201 demonstrated low levels of degradation in 22RV-1cells.

These SARD activity demonstrations suggest the compounds of thisinvention are able to degrade a variety of AR variants, and hence shouldprovide the ability to inhibit the AR-axis activity whether it isandrogen-dependent or androgen-independent. Degradation of the ARremoves the possibility of promiscuous activation of mutant ARs,activation by intracellular processes such as signal transduction andkinase activation, etc.; and suggests that the SARDs should also degradethe polyQ polymorphism in hyperandrogenic dermatologic disorders(shortened polyQ) or Kennedy's disease (extended polyQ), providing arationale for treating either type of diseases by destroying the AR inthe affected tissues (skin and neuromuscular system, respectively).

Example 15 Further Studies with SARDs

PCa Gene Expression and Cell Growth:

PCa cells (LNCaP and 22RV1) will be plated at 10,000 cells per well of a96 well plate in respective medium supplemented with 1% csFBS or in fullserum. The cells will be maintained for 3 days and will be treated withSARDs or controls alone or in combination with 0.1 nM R1881 (1% csFBS).RNA will be isolated and cDNA prepared using cells-to-ct kits (LifeTechnologies). Expression of various androgen-regulated genes will bemeasured using TaqMan primer probe mix on an ABI 7900 realtime PCRmachine. The expression of individual genes will be normalized to 18SrRNA levels.

PCa cells will be plated at 10,000 cells per well of a 96 well plate inrespective medium supplemented with 1% csFBS or in full serum. The cellswill be treated with SARDs alone or in combination with 0.1 nM R1881.The cell viability will be measured using Sulforhodamine blue reagent.As negative control, AR-negative PC3 cells will be treated similarly toensure the absence of any non-specific growth inhibitory properties ofSARDs.

Preclinical Rodent Pharmacokinetic (PK) Studies:

The PK parameters of SARDs in various formulations will be determined inrats and mice as appropriate. Approximately 250 gram Sprague-Dawley ratswill be randomized into groups of 5 and a catheter surgically implantedinto the jugular vein. After a recovery period the rats will beadministered test compound and 250 μL of venous blood will be seriallysampled from the catheter at 0, 10, 20, 30, 60, 120, 240, 480, 720, 1440and 2880 minutes post administration for an intravenous dose or 0, 20,40, 60, 90, 120, 150, 180, 210, 240, 480, 720, 1440, and 2880 minutespost administration for a non-intravenous dose. For mice, approximately20 gram C57BL/6 mice will be grouped into three per time point per routeof administration. Following administration of an intravenous dose micewill be sacrificed and blood collected by cardiac puncture at 0, 10, 20,30, 60, 120, 240, 480, 720, 1440 and 2880 minutes after intravenousdosing or 0, 30, 60, 90, 120, 150, 180, 210, 240, 480, 720, 1440, 2880minutes after dosing for a non-intravenous dose. Samples will becollected in appropriate anti-coagulant containing tubes and plasmaprepared for LC-MS-MS analyses. Relevant PK parameters will be estimatedvia non-compartmental analyses using Phoenix WinNonlin.

PCa Xenograft Studies:

Nod Scid γ (NSG)/nude mice (6-8 weeks in age) will be used in thexenograft experiments. Briefly, a mixture of 1:1 LNCaP or 22RV-1 cellsin medium (10% FBS supplemented medium):matrigel mixture will beimplanted subcutaneously in male NSG mice. Cell number to be implantedwill depend on the cell type. Tumors will be implanted in male nude micethat have high circulating androgens or in castrated animalssupplemented with DHT to streamline the hormone circulation and toreduce variability between animals. For CRPC model, animals will becastrated when VCaP tumors reach 100 mm³ and the tumors will be allowedto re-grow as CRPC. Animals will be randomized into groups once thetumors reach 200 mm³ and will be treated daily with vehicle orrespective SARD. Tumor volume will be measured thrice weekly and theanimals will be sacrificed at the end of the study. At sacrifice, tumorswill be weighed and stored for further histological and molecularbiological analysis. Tumor volume will be calculated using the formulalength×width×width×0.5236.

Example 16 In Vivo Studies of SARDs

Hershberger Assay:

Mice (6-7 weeks old) were treated with vehicle or indicated SARDs (100mg/kg/day twice daily) for 14 days orally. Animals were sacrificed andseminal vesicles weights were recorded and represented.

Results:

SARDs 11, 34, 37, 38, 103, and 115 demonstrated varying levels ofinhibition of seminal vesicles growth. 103 had the greatest effect of SV(FIG. 30A and FIG. 30D), prostate (FIG. 30C), and also had an effect ofbody weight (FIG. 30B).

SARDs were also investigated in xenograft studies. 103 demonstrated lowlevels of efficacy in patient derived (FIG. 31) and mouse (FIG. 32)xenografts despite very low levels in the plasma.

TABLE 14 SARDs are detected in plasma and tumor. Conc of 103 (nM) PlasmaSample #768 3.81 Plasma Sample #769 18.4 Tumor Sample #768 142 TumorSample #769 282 Calibration Curve Range 1.95-2000 Nm R² 0.9957Regression Quadratic Weighting 1/x²

However, unexpectedly 103 was found to accumulate in the tumor, possiblyexplaining it activity (see chart above). SARDs selectively accumulatein tumor: NSG mice were implanted with patient-derived prostate cancerxenograft. Animals were treated for 14 days and tumor volumes weremeasured twice weekly. Animals were sacrificed, 103 extracted from serumand tumor and measured using LC-MS/MS method.

103 selectively accumulates in tumor with almost 10 times more tumoraccumulation than in plasma. (FIG. 31). While 103 had weak activity intumor xenografts, 36 demonstrated promising inhibition of tumor growth.

What is claimed is:
 1. A selective androgen receptor degrader (SARD)compound represented by the structure of formula I:

wherein W₁ and W₂ are each independently selected from N or CH; W₃, W₄,W₅ and W₆ are each independently selected from CH or N; wherein if anyone of W₁, W₂, W₃, W₄, W₅, and W₆ is CH, then the H is optionallyreplaced with R₄, Q or R₃ in the respective position, and if any one ofW₁, W₂, W₃, W₄, W₅, and W₆ is not CH, then the respective position isunsubstituted; T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₄ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, alkoxy, haloalkyl, optionallysubstituted linear or branched alkyl, optionally substituted linear orbranched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; n is an integer between 1-3; and m is an integerbetween 1-3 The SARD compound according to claim 1, wherein W₁, W₂, W₃,W₄, W₅, and W₆ are CH.
 2. The SARD compound according to claim 1,wherein W₂ is N and W₁, W₃, W₄, W₅, and W₆ are CH.
 3. The SARD compoundaccording to claim 1, wherein W₃ is N and W₁, W₂, W₄, W₅, and W₆ are CH.4. The SARD compound according to claim 1, wherein W₁=N and W₂, W₃, W₄,W₅, W₆ are CH.
 5. The SARD compound according to claim 1, represented bythe structure of formula III:


6. The SARD compound of claim 1, wherein Q is H, NO₂, COR, alkyl,alkoxy, aryl, CN, CF₃, F, Cl, Br or I.
 7. The SARD compound of claim 1,wherein Z is CN.
 8. The SARD compound of claim 1, wherein Y is Cl orCF₃.
 9. The SARD compound of claim 1, represented by the structure ofthe following compounds:

Benzimidazoles:

Pyrrolo-pyridine:

Indazoles:


10. A pharmaceutical composition comprising a SARD compound according toclaim 1, or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof, and apharmaceutically acceptable carrier.
 11. The pharmaceutical compositionof claim 10, wherein said composition is formulated for topical use. 12.The pharmaceutical composition of claim 10, wherein said composition isin the form of a solution, lotion, salve, cream, ointment, liposome,spray, gel, foam, roller stick, cleansing soaps or bars, emulsion,mousse, aerosol, shampoo, or any combination thereof.
 13. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound according to claim 1, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 14. The method of claim 13, whereinthe prostate cancer is advanced prostate cancer, castration resistantprostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC(nmCRPC), high-risk nmCRPC or any combination thereof.
 15. The method ofclaim 13, wherein said subject further receives androgen deprivationtherapy (ADT).
 16. The method of claim 13, wherein said subject hasfailed androgen deprivation therapy (ADT).
 17. The method of claim 13,wherein said cancer is resistant to treatment with an androgen receptorantagonist.
 18. The method of claim 13, wherein said administeringreduces the levels of AR, AR-full length (AR-FL), AR-FL withantiandrogen resistance-conferring AR-LBD mutations, AR-splice variant(AR-SV), or any combination thereof, in said subject.
 19. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of Kennedy's disease in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 1, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.20. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of acne in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 1, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof.
 21. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofhirsutism in a subject, comprising administering to said subject atherapeutically effective amount of the compound of claim 1, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 22. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of alopecia in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 1, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.23. The method of claim 22, wherein said alopecia is androgenicalopecia, alopecia areata, alopecia secondary to chemotherapy, alopeciasecondary to radiation therapy, alopecia induced by scarring, alopeciainduced by stress or any combination thereof.
 24. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hormonal condition in a female,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 1 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof.
 25. The method of claim 24, wherein said hormonalcondition is precocious puberty, early puberty, dysmenorrhea,amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma,abnormal uterine bleeding, early menarche, fibrocystic breast disease,fibroids of the uterus, ovarian cysts, polycystic ovary syndrome,pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrualsyndrome, and/or vaginal dryness.
 26. A method of treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of sexual perversion, hypersexuality, or paraphilias in asubject, comprising administering to said subject a therapeuticallyeffective amount of the compound of claim 1, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 27. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 1, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof.
 28. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofvirilization in a subject, comprising administering to said subject atherapeutically effective amount of the compound of claim 1, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 29. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndrome in asubject, comprising administering to said subject a therapeuticallyeffective amount of the compound of claim 1, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 30. A method of increasing,modulating, or improving ovulation in an animal, comprisingadministering to said animal a therapeutically effective amount of thecompound of claim 1, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.31. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of cancer in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of 1, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof.
 32. The method of claim 30, wherein said cancer is breastcancer, testicular cancer, uterine cancer, ovarian cancer, urogenitalcancer, brain cancer, skin cancer, lymphoma, liver cancer, renal cancer,osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer,non-small cell lung cancer (NSCLC), colon cancer, perianal adenomas,central nervous system cancer, or any combination thereof.
 33. A methodof treating, suppressing, reducing the incidence, reducing the severity,or inhibiting the progression of amyotrophic lateral sclerosis (ALS) ina subject, comprising administering to said subject a therapeuticallyeffective amount of the compound of claim 1, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 34. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 1, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.35. A selective androgen receptor degrader (SARD) compound representedby the structure of formula V:

wherein T is OH, OR, —NHCOCH₃, NHCOR or

Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl, CN orC(R)₃; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is hydrogen, halogen, CN, NO₂, COOH,COOR, COR, NHCOR, CONHR, OH, OR, SH, SR, NH₂, NHR, NR₂, C₁-C₁₂-alkyl,C₁-C₁₂-haloalkyl, O—C₁-C₁₂-alkyl, O—C₁-C₁₂-haloalkyl, —SO₂-aryl,—SO₂-phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl; Qis hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, COOH, COOR, alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; R₃ is hydrogen, F, Cl, Br, I, CF₃, CN, NO₂, NH₂, SH,COOH, COOR, alkoxy, haloalkyl, optionally substituted linear or branchedalkyl, optionally substituted linear or branched heteroalkyl, optionallysubstituted aryl, optionally substituted phenyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR,NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR,COR, OCOR, OSO₂R, SO₂R, SR, NCS, SCN, NCO or OCN; R₄ is hydrogen, F, Cl,Br, I, CF₃, CN, NO₂, NH₂, SH, COOH, COOR, keto (═O), alkoxy, haloalkyl,optionally substituted linear or branched alkyl, optionally substitutedlinear or branched heteroalkyl, optionally substituted aryl, optionallysubstituted phenyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylalkyl, C(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR, NCS,SCN, NCO or OCN; n is an integer between 1-3; m is an integer between1-3; l is 0 or 1; and k is 0, 1 or
 2. 36. The SARD compound of claim 34,wherein said compound is represented by the structure of formula VI:


37. The SARD compound of claim 34, wherein said compound is representedby the structure of formula VII:


38. The SARD compound of claim 34, wherein said compound is representedby the structure of formula IV:


39. The SARD compound of claim 34, wherein Q is CN.
 40. The SARDcompound of claim 34, wherein said compound is represented by thefollowing structures: Indolines

Isoquinolines and Quinolines


41. A pharmaceutical composition comprising a SARD compound according toclaim 35, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,and a pharmaceutically acceptable carrier.
 42. The pharmaceuticalcomposition of claim 35, wherein said composition is formulated fortopical use.
 43. The pharmaceutical composition of claim 42, whereinsaid composition is in the form of a solution, lotion, salve, cream,ointment, liposome, spray, gel, foam, roller stick, cleansing soaps orbars, emulsion, mousse, aerosol, shampoo, or any combination thereof.44. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of prostate cancer (PCa) andits symptoms, or increasing the survival of a male subject sufferingfrom prostate cancer comprising administering to said subject atherapeutically effective amount of a compound according to claim 35, orits isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 45. The method of claim44, wherein the prostate cancer is advanced prostate cancer, castrationresistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof.
 46. The method of claim 44 wherein said subject furtherreceives androgen deprivation therapy (ADT).
 47. The method of claim 44,wherein said subject has failed androgen deprivation therapy (ADT). 48.The method of claim 44, wherein said cancer is resistant to treatmentwith an androgen receptor antagonist.
 49. The method of claim 44,wherein said administering reduces the levels of AR, AR-full length(AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations,AR-splice variant (AR-SV), or any combination thereof, in said subject.50. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of Kennedy's disease in asubject, comprising administering to said subject a therapeuticallyeffective amount of the compound of claim 35, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 51. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 35, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.52. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of hirsutism in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 35, or its isomer, pharmaceuticalacceptable saltpharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 53. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of alopecia in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 35, or its isomer, pharmaceutical acceptablesaltpharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 54. The method of claim 53, whereinsaid alopecia is androgenic alopecia, alopecia areata, alopeciasecondary to chemotherapy, alopecia secondary to radiation therapy,alopecia induced by scarring, alopecia induced by stress or anycombination thereof.
 55. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression of ahormonal condition in a female, comprising administering to said subjecta therapeutically effective amount of the compound of claim 35 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 56. The method of claim55, wherein said hormonal condition is precocious puberty, earlypuberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome,endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche,fibrocystic breast disease, fibroids of the uterus, ovarian cysts,polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, and/or vaginal dryness.
 57. Amethod of treating, suppressing, reducing the incidence, reducing theseverity, or inhibiting the progression of sexual perversion,hypersexuality, or paraphilias in a subject, comprising administering tosaid subject a therapeutically effective amount of the compound of claim35, or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 58. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 35, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof.
 59. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofvirilization in a subject, comprising administering to said subject atherapeutically effective amount of the compound of claim 35, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 60. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndrome in asubject, comprising administering to said subject a therapeuticallyeffective amount of the compound of claim 35, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof.
 61. A method of increasing,modulating, or improving ovulation in an animal, comprisingadministering to said animal a therapeutically effective amount of thecompound of claim 35, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.62. A method of treating, suppressing, reducing the incidence, reducingthe severity, or inhibiting the progression of cancer in a subject,comprising administering to said subject a therapeutically effectiveamount of the compound of claim 35, or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof.
 63. The method of claim 62, wherein said cancer isbreast cancer, testicular cancer, uterine cancer, ovarian cancer,urogenital cancer, brain cancer, skin cancer, lymphoma, liver cancer,renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lungcancer, non-small cell lung cancer (NSCLC), colon cancer, perianaladenoma, central nervous system cancer, or any combination thereof. 64.A method of treating, suppressing, reducing the incidence, reducing theseverity, or inhibiting the progression of amyotrophic lateral sclerosis(ALS) in a subject, comprising administering to said subject atherapeutically effective amount of the compound of claim 35, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.
 65. A method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering to said subject a therapeutically effective amount of thecompound of claim 35, or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.